US8916165B2 - Humanized Aβ antibodies for use in improving cognition - Google Patents
Humanized Aβ antibodies for use in improving cognition Download PDFInfo
- Publication number
- US8916165B2 US8916165B2 US11/303,478 US30347805A US8916165B2 US 8916165 B2 US8916165 B2 US 8916165B2 US 30347805 A US30347805 A US 30347805A US 8916165 B2 US8916165 B2 US 8916165B2
- Authority
- US
- United States
- Prior art keywords
- antibody
- seq
- heavy chain
- variable region
- humanized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- OWUHJCKZGIQVDI-UHFFFAOYSA-N C.C.[Ag] Chemical compound C.C.[Ag] OWUHJCKZGIQVDI-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- Memory is a key cognitive function involving the storage and/or retrieval by the brain of information received from past experiences.
- Learning also referred to as conditioning, is the process by which new information is acquired and stored by the nervous system to form a memory.
- the cognitive pathways for learning and/or memory are impaired, such that the patient fails to learn or effectively form new memories or recall old ones.
- the number of individuals exhibiting dementia is rising rapidly, and the rate of rise is expected to increase as the general population continues to age and life expectancy continues to lengthen.
- Patients with dementia require increasingly costly and intensive caregiving as their symptoms worsen.
- medical interventions that delay institutionalization would help reduce the demands on healthcare systems, in addition to alleviating the sufferings of the subject with the dementia.
- AD Alzheimer's disease
- Neurodegeneration is associated with amyloidogenic disorders and other dementia disorders such that the cognitive symptoms progressively worsen with age.
- the diagnosis of an amyloidogenic disorder can usually only be confirmed by the distinctive cellular pathology that is evident on post-mortem examination of the brain.
- the histopathology consists of at least one of three principal features including the presence of neurofibrillary tangles (NT), the diffuse loss of synapses and neurons in central nervous system tissues, and the presence of amyloid plaques (also called senile plaques).
- NT neurofibrillary tangles
- senile plaques also called senile plaques.
- a ⁇ or ⁇ -amyloid peptide The principal constituent of the plaques is a peptide termed A ⁇ or ⁇ -amyloid peptide.
- a ⁇ peptide is an approximately 4-kDa internal fragment of 39-43 amino acids of a larger transmembrane glycoprotein named protein termed amyloid precursor protein (APP).
- APP amyloid precursor protein
- a ⁇ is primarily found in both a short form, 40 amino acids in length, and a long form, ranging from 4243 amino acids in length.
- Part of the hydrophobic transmembrane domain of APP is found at the carboxy end of A ⁇ , and may account for the ability of A ⁇ to aggregate into plaques, particularly in the case of the long form. Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death. The physical symptoms associated with this type of neural deterioration characterize AD.
- Such mutations are thought to cause AD by increased or altered processing of APP to A ⁇ , particularly processing of APP to increased amounts of the long form of A ⁇ (i.e., A ⁇ 1-42 and A ⁇ 1-43).
- Mutations in other genes, such as the presenilin genes, PS1 and PS2 are thought indirectly to affect processing of APP to generate increased amounts of long form A ⁇ (see Hardy, TINS 20: 154 (1997)).
- a ⁇ peptide can exist in solution and can be detected in the central nervous system (CNS) (e.g., in cerebral spinal fluid (CSF)) and plasma. Under certain conditions, soluble A ⁇ is transformed into fibrillary, toxic, ⁇ -sheet forms found in neuritic plaques and cerebral blood vessels of patients with AD.
- CNS central nervous system
- CSF cerebral spinal fluid
- soluble A ⁇ is transformed into fibrillary, toxic, ⁇ -sheet forms found in neuritic plaques and cerebral blood vessels of patients with AD.
- Several treatments have been developed which attempt to prevent the formation of A ⁇ peptide, for example, the use of chemical inhibitors to prevent the cleavage of APP. Immunotherapeutic treatments have also been investigated as a means to reduce the density and size of existing plaques.
- the central degradation mechanism relies on antibodies being able to cross the blood-brain barrier, bind to plaques, and induce clearance of pre-existing plaques. Clearance has been shown to be promoted through an Fc-receptor-mediated phagocytosis (Bard, et al. (2000) Nat. Med. 6:916-19).
- the peripheral degradation mechanism of A ⁇ clearance relies on a disruption of the dynamic equilibrium of A ⁇ between brain, CSF, and plasma by anti-A ⁇ antibodies, leading to transport of A ⁇ from one compartment to another. Centrally derived A ⁇ is transported into the CSF and the plasma where it is degraded.
- the present invention features immunological reagents, in particular, therapeutic antibody reagents for the prevention and treatment of A ⁇ -related diseases or disorders and/or amyloidogenic diseases or disorders (e.g., AD).
- the invention is based, at least in part, on the identification and characterization of a monoclonal antibody, 12A11, that specifically binds to A ⁇ peptide and is effective at reducing plaque burden associated with amyloidogenic disorders (e.g., AD). 12A11 also exhibits preferential binding for soluble oligomeric A ⁇ and is effective at improving cognition in an animal model of AD. Structural and functional analysis of this antibody leads to the design of various humanized antibodies for prophylactic and/or therapeutic use.
- the invention features humanization of the variable regions of this antibody and, accordingly, provides for humanized immunoglobulin or antibody chains, intact humanized immunoglobulins or antibodies, and functional immunoglobulin or antibody fragments, in particular, antigen binding fragments, of the featured antibody.
- the present invention features immunological reagents and improved methods for preventing or treating AD or other amyloidogenic diseases.
- the invention is based, at least in part, on the characterization of a monoclonal immunoglobulin, 12A11, effective at binding beta amyloid protein (A ⁇ ) (e.g., binding soluble and/or aggregated A ⁇ ), mediating phagocytosis (e.g., of aggregated A ⁇ ), reducing plaque burden, reducing neuritic dystrophy and/or improving cognition (e.g., in a subject).
- a ⁇ beta amyloid protein
- mediating phagocytosis e.g., of aggregated A ⁇
- reducing plaque burden reducing neuritic dystrophy
- improving cognition e.g., in a subject.
- the invention is further based on the determination and structural characterization of the primary and secondary structure of the variable light and heavy chains of the 12A11 immunoglobulin and the identification of residues important for activity and immunogenicity.
- Immunoglobulins are featured which include a variable light and/or variable heavy chain of the 12A11 monoclonal immunoglobulin described herein.
- Preferred immunoglobulins e.g., therapeutic immunoglobulins, are featured which include a humanized variable light and/or humanized variable heavy chain.
- Preferred variable light and/or variable heavy chains include a complementarity determining region (CDR) from the 12A11 immunoglobulin (e.g., donor immunoglobulin) and variable framework regions from or substantially from a human acceptor immunoglobulin.
- CDR complementarity determining region
- substantially from a human acceptor immunoglobulin means that the majority or key framework residues are from the human acceptor sequence, allowing however, for substitution of residues at certain positions with residues selected to improve activity of the humanized immunoglobulin (e.g., alter activity such that it more closely mimics the activity of the donor immunoglobulin) or selected to decrease the immunogenicity of the humanized immunoglobulin.
- the invention features a humanized immunoglobulin light or heavy chain that includes 12A11 variable region complementarity determining regions (CDRs) (i.e., includes one, two or three CDRs from the light chain variable region sequence set forth as SEQ ID NO:2 or includes one, two or three CDRs from the heavy chain variable region sequence set forth as SEQ ID NO:4), and includes a variable framework region from a human acceptor immunoglobulin light or heavy chain sequence, optionally having at least one residue of the framework residue backmutated to a corresponding murine residue, wherein said backmutation does not substantially affect the ability of the chain to direct A ⁇ binding.
- CDRs 12A11 variable region complementarity determining regions
- the invention features a humanized immunoglobulin light or heavy chain that includes 12A11 variable region complementarity determining regions (CDRs) (i.e., includes one, two or three CDRs from the light chain variable region sequence set forth as SEQ ID NO:2 or includes one, two or three CDRs from the heavy chain variable region sequence set forth as SEQ ID NO:4), and includes a variable framework region substantially from a human acceptor immunoglobulin light or heavy chain sequence, optionally having at least one residue of the framework residue backmutated to a corresponding murine residue, wherein said backmutation does not substantially affect the ability of the chain to direct A ⁇ binding.
- CDRs 12A11 variable region complementarity determining regions
- the invention features a humanized immunoglobulin light or heavy chain that includes 12A11 variable region complementarity determining regions (CDRs) (e.g., includes one, two or three CDRs from the light chain variable region sequence set forth as SEQ ID NO:2 and/or includes one, two or three CDRs from the heavy chain variable region sequence set forth as SEQ ID NO:4), and includes a variable framework region substantially from a human acceptor immunoglobulin light or heavy chain sequence, optionally having at least one framework residue substituted with the corresponding amino acid residue from the mouse 12A11 light or heavy chain variable region sequence, where the framework residue is selected from the group consisting of (a) a residue that non-covalently binds antigen directly; (b) a residue adjacent to a CDR; (c) a CDR-interacting residue (e.g., identified by modeling the light or heavy chain on the solved structure of a homologous known immunoglobulin chain); and (d) a residue participating in the VL-VH interface.
- the invention features a humanized immunoglobulin light or heavy chain that includes 12A11 variable region CDRs and variable framework regions from a human acceptor immunoglobulin light or heavy chain sequence, optionally having at least one framework residue substituted with the corresponding amino acid residue from the mouse 12A11 light or heavy chain variable region sequence, where the framework residue is a residue capable of affecting light chain variable region conformation or function as identified by analysis of a three-dimensional model of the variable region, for example a residue capable of interacting with antigen, a residue proximal to the antigen binding site, a residue capable of interacting with a CDR, a residue adjacent to a CDR, a residue within 6 ⁇ of a CDR residue, a canonical residue, a vernier zone residue, an interchain packing residue, a rare residue, or a glycoslyation site residue on the surface of the structural model.
- the framework residue is a residue capable of affecting light chain variable region conformation or function as identified by analysis of a three-dimensional model of the variable region
- the invention features, in addition to the substitutions described above, a substitution of at least one rare human framework residue.
- a rare residue can be substituted with an amino acid residue which is common for human variable chain sequences at that position.
- a rare residue can be substituted with a corresponding amino acid residue from a homologous germline variable chain sequence.
- the invention features a humanized immunoglobulin that includes a light chain and a heavy chain, as described above, or an antigen-binding fragment of said immunoglobulin.
- the humanized immunoglobulin binds (e.g., specifically binds) to beta amyloid peptide (A ⁇ ) with a binding affinity of at least 10 7 M ⁇ 1 , 10 ⁇ 8 M ⁇ 1 , or 10 9 M ⁇ 1 .
- the immunoglobulin or antigen binding fragment includes a heavy chain having isotype ⁇ 1.
- the immunoglobulin or antigen binding fragment binds (e.g., specifically binds) to either or both soluble beta amyloid peptide (A ⁇ ) and aggregated A ⁇ .
- the immunoglobulin or antigen binding fragment captures soluble A ⁇ (e.g., soluble A ⁇ 1-42).
- the immunoglobulin or antigen binding fragment mediates phagocytosis (e.g., induces phagocytosis) of beta amyloid peptide (A ⁇ ).
- the immunoglobulin or antigen binding fragment crosses the blood-brain barrier in a subject.
- the immunoglobulin or antigen binding fragment reduces either or both beta amyloid peptide (A ⁇ ) burden and neuritic dystrophy in a subject.
- the invention features chimeric immunoglobulins that include 12A11 variable regions (e.g., the variable region sequences set forth as SEQ ID NO:2 or SEQ ID NO:4).
- the immunoglobulin, or antigen-binding fragment thereof further includes constant regions from IgG1.
- the immunoglobulins described herein are particularly suited for use in therapeutic methods aimed at preventing or treating A ⁇ -related disease or disorders or amyloidogenic diseases or disorders.
- the invention features a method of preventing or treating amyloidogenic diseases or disorders (e.g., AD) that involve administering to the patient an effective dosage of a humanized immunoglobulin as described herein.
- the invention features therapeutic and/or prophylactic methods effective in preventing or ameliorating the dementia and/or cognitive deficits that are observed in patients with neurodegenerative diseases or disorders (e.g., A ⁇ -related disease or disorders).
- the invention provides improved therapeutic and/or prophylactic methods comprising administration of therapeutic agents that interfere with early steps in the pathogenesis of the diseases or disorders and prevent irreversible neural damage and/or dementia.
- Featured aspects of the present invention provide methods for rapidly improving cognition in a subject that involve administration of a 12A11 immunological reagent, or pharmaceutical composition comprising said reagent.
- Preferred 12A11 immunological reagents include, but are not limited to 12A11 antibodies, humanized 12A11 antibodies, chimeric 12A11 antibodies, single-chain 12A11 antibodies, bispecific 12A11 antibodies, 12A11 antibody fragments, 12A11 antibody chains, variants thereof (e.g. 12A11 Fc antibody variants), or combinations thereof.
- Another aspect of the invention features methods for effecting prolonged improvement of cognition in a subject that involve administration of a 12A11 immunological reagent or pharmaceutical composition comprising said reagent.
- the methods of the invention involve the administration of a 12A11 immunological reagent, which is effective at binding A ⁇ , in particular, A ⁇ oligomers, reducing amyloid burden, and/or rapidly improving cognition in a subject suffering from a dementia disease or disorder, e.g. an A ⁇ -related disease or disorder.
- a 12A11 immunological reagent which is effective at binding A ⁇ , in particular, A ⁇ oligomers, reducing amyloid burden, and/or rapidly improving cognition in a subject suffering from a dementia disease or disorder, e.g. an A ⁇ -related disease or disorder.
- the methods of the invention feature polypeptides comprising the complementarity determining regions (CDRs) of a 12A11 monoclonal antibody, including polynucleotide reagents, vectors and host cells suitable encoding said polypeptides.
- CDRs complementarity determining regions
- the invention features pharmaceutical compositions that include a humanized immunoglobulin as described herein and a pharmaceutical carrier. Also featured are isolated nucleic acid molecules, vectors and host cells for producing the immunoglobulins or immunoglobulin fragments or chains described herein, as well as methods for producing said immunoglobulins, immunoglobulin fragments or immunoglobulin chains.
- the present invention further features methods for identifying 12A11 residues amenable to substitution when producing a humanized 12A11 immunoglobulin, respectively.
- a method for identifying variable framework region residues amenable to substitution involves modeling the three-dimensional structure of a 12A11 variable region on a solved homologous immunoglobulin structure and analyzing said model for residues capable of affecting 12A11 immunoglobulin variable region conformation or function, such that residues amenable to substitution are identified.
- the invention further features use of the variable region sequence set forth as SEQ ID NO:2 or SEQ ID NO:4, or any portion thereof, in producing a three-dimensional image of a 12A11 immunoglobulin, 12A11 immunoglobulin chain, or domain thereof.
- the present invention further features immunoglobulins having altered effector function, such as the ability to bind effector molecules, for example, complement or a receptor on an effector cell.
- the immunoglobulin of the invention has an altered constant region, e.g., Fc region, wherein at least one amino acid residue in the Fc region has been replaced with a different residue or side chain.
- the modified immunoglobulin is of the IgG class, comprises at least one amino acid residue replacement in the Fc region such that the immunoglobulin has an altered effector function, e.g., as compared with an unmodified immunoglobulin.
- an immunoglobulin of the invention has an altered effector function such that it is less immunogenic (e.g., does not provoke undesired effector cell activity, lysis, or complement binding), has improved amyloid clearance properties, and/or has a desirable half-life.
- an immunoglobulin of the invention comprises one or more amino acid alterations in the hinge region, for example, at EU positions 234, 235, 236 and 237.
- an immunoglobulin according to the invention is a humanized 12A11 antibody including amino acid alterations at positions 234 and 237 of the hinge link region (i.e., L234A and G237A).
- immunoglobulins of the invention comprise pegylated antibody fragments, e.g., Fabs and Fab's. In yet other embodiments, immunoglobulins of the invention comprise an aglycosylated constant region. In an exemplary embodiment, an immunoglobulin includes an amino acid substitution of an asparagine at position 297 to an alanine, thereby preventing glycosylation of the immunoglobulin.
- Also featured herein are methods of increasing expression of immunoglobulins by deleting one or more introns in a gene which encodes the heavy chain of the immunoglobulin.
- this invention relates to methods of treatment, as described herein, using one or more immunoglobulins of the invention.
- FIG. 1 graphically depicts results from an experiment which examines the effectiveness of various antibodies, including 12A11, at clearing A ⁇ plaques in an ex vivo phagocytosis assay.
- FIG. 2A graphically depicts results from an experiment which examines the effectiveness of various antibodies, including 12A11, at reducing total A ⁇ levels. The bars represent median values, and the dashed horizontal line indicates the control level.
- FIG. 2B graphically depicts results from an experiment which analyzes the effectiveness of various antibodies, including 12A11, at reducing neuritic dystrophy. The bars represent median values, and the dashed horizontal line indicates the control level. Data are shown for individual animals and expressed as the percentage of neuritic dystrophy relative to the mean of the control (set at 100%).
- FIG. 3 depicts a Western blot of immunoprecipitates of peroxynitrite treated oligomeric A ⁇ 1-42 preparation precipitated with various A ⁇ antibodies (3D6, 6C6, 12A11, 12B4, 3A3, 266, 9G8, 15C11, and 6H9) and imaged with 3D6.
- a ⁇ antibodies 3D6, 6C6, 12A11, 12B4, 3A3, 266, 9G8, 15C11, and 6H9
- the approximate positions of A ⁇ 1-42 monomer, dimer, trimer and tetramer bands are indicated on the left-hand side of the figure.
- each A ⁇ antibody is the A ⁇ epitope recognized by the antibody and Contextual Fear Conditioning (CFC) assay results for the antibody
- CFC Contextual Fear Conditioning
- a “+” notation indicates an observation of increased cognition upon treatment with the antibody
- a “ ⁇ ” notation indicates an observation of no change in cognition upon treatment with the antibody
- a “+/ ⁇ ” notation indicates an observation of a trend of increased cognition upon treatment with the antibody but the observed trend was not statistically significant enough to be indicated as an observation of increased cognition
- “ND” notation indicates no CFC assay data compared for this antibody.
- FIG. 4 depicts a Western blot of immunoprecipitates of peroxynitrite treated oligomeric A ⁇ 1-42 preparation precipitated with various A ⁇ antibodies (3D6, 6C6, 12A11, 12B4, 10D5, 3A3, 266 and 6H9) and imaged with 3D6. Annotation is the same as for FIG. 3 .
- FIG. 5A depicts the results of a CFC assay in which rapid improvement in cognition is observed following the administration of single doses of murine 12A11 (1, 10, and 30 mg/kg) to Tg2576 mice.
- FIG. 5B depicts the results of a CFC assay in which rapid improvement in cognition is observed following the administration of single, low doses of murine 12A11 (0.3 and 1 mg/kg) to Tg2576 mice.
- FIG. 6 depicts the results of a study in which the duration of improved cognition following the administration of a single dose of murine 12A11 (1 mg/kg) is assessed at 1, 10, and 17 days post-administration in a contextual fear conditioning (CFC) assay.
- CFC contextual fear conditioning
- FIG. 7A depicts a DNA sequence including the murine 12A11 VL chain sequence and the deduced amino acid sequence for the VL chain (SEQ ID NOS 5 and 2, respectively). Mature VL chain is indicated by a solid black bar. CDRs are indicated by open bars. DNA sequences include cloning sites and Kozak sequences (upstream of coding sequences) and splice and cloning sequences (downstream).
- FIG. 7B depicts a DNA sequence including the murine 12A11 VH chain and the deduced amino acid sequence for the VH chain (SEQ ID NOS 6 and 4, respectively). Mature VH chain is indicated by a solid black bar. CDRs are indicated by open bars.
- FIG. 8 graphically depicts the ELISA results from an experiment measuring the binding of chimeric 12A11, chimeric and humanized 3D6 (h3D6), and chimeric and humanized 12B4 to A ⁇ 142.
- FIG. 9A depicts an alignment of the amino acid sequences of the light chain of murine (or chimeric) 12A11 (SEQ ID NO:2), humanized 12A11 (mature peptide, SEQ ID NO:7), GenBank BAC01733 (SEQ ID NO: 8) and germline A9 (X63397, SEQ ID NO: 9) antibodies. CDR regions are boxed. Packing residues are underlined. Numbered from the first methionine, not Kabat numbering.
- FIG. 9A depicts an alignment of the amino acid sequences of the light chain of murine (or chimeric) 12A11 (SEQ ID NO:2), humanized 12A11 (mature peptide, SEQ ID NO:7), GenBank BAC01733 (SEQ ID NO: 8) and germline A9 (X63397, SEQ ID NO: 9) antibodies. CDR regions are boxed. Packing residues are underlined. Numbered from the first methionine, not Kabat numbering.
- 9B depicts an alignment of the amino acid sequences of the heavy chain of murine (or chimeric) 12A11 (SEQ ID NO:4), humanized 12aA11 (version 1) (mature peptide, SEQ ID NO:10), GenBank AAA69734 (SEQ ID NO:11), and germline GenBank 567123 antibodies (SEQ ID NO:12). Packing residues are underlined, canonical residues are in solid fill and vernier residues are in dotted fill. Numbered from the first methionine, not Kabat numbering.
- FIG. 10A-B depicts an alignment of the amino acid sequences of the heavy chains of humanized 12A11 v1 (SEQ ID NO:10), v2 (SEQ ID NO:13), v2.1 (SEQ ID NO:14), v3 (SEQ ID NO:15), v3.1 (SEQ ID NO:36), v4.1 (SEQ ID NO:16), v4.2 (SEQ ID NO:17), v4.3 (SEQ ID NO:18), v4.4 (SEQ ID NO:19), v5.1 (SEQ ID NO:20), v5.2 (SEQ ID NO:21), v5.3 (SEQ ID NO:22), v5.4 (SEQ ID NO:23), v5.5 (SEQ ID NO:24), v5.6 (SEQ ID NO:25), v6.1 (SEQ ID NO:26), v6.2 (SEQ ID NO:27), v6.3 (SEQ ID NO:28), v6.4 (SEQ ID NO:29), v7 (SEQ ID NO:30) and v8 (SEQ ID
- FIG. 11 depicts the results from an aggregated A ⁇ (142) ELISA comparing chimeric 12A11, humanized 12A11 v1, humanized 12A11 v2, humanized 12A11 v2.1, and humanized 12A11 v3.
- FIG. 12 depicts the results of a competitive A ⁇ 1-42 ELISA binding assay comparing murine 12A11, chimeric 12A11 and h12A11 v1.
- FIG. 13 depicts the results of a competitive A ⁇ 1-42 ELISA binding assay comparing murine 12A11, chimeric 12A11, h12A11 v1, h12A11 v2, h12A11 v3, and h12A11 v3.1.
- FIG. 14 depicts the results of a CFC assay in which rapid improvement in cognition is observed following the administration of single doses of the humanized 12A11 antibody v3.1 h12A11 (1, 10, and 30 mg/kg) to Tg2576 mice.
- a ⁇ -related disease or disorder refers to a disease or disorder associated with, or characterized by, the development or presence of an A ⁇ peptide.
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of soluble A ⁇ .
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of insoluble A ⁇ .
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of a neuroactive A ⁇ species (NA ⁇ ).
- NA ⁇ neuroactive A ⁇ species
- the A ⁇ -related disease or disorder is also an amyloidogenic disorder.
- the A ⁇ -related disease or disorder is characterized by an A ⁇ -related cognitive deficit or disorder, for example, an A ⁇ -related dementia disorder.
- Exemplary A ⁇ -related diseases or disorders include Alzheimer's disease (AD), Down's syndrome, cerebral amyloid angiopathy, certain vascular dementias, and mild cognitive impairment (MCI).
- AP peptide e.g., A ⁇ 39, A ⁇ 40, A ⁇ 41, A ⁇ 42 and A ⁇ 3
- APP Amyloid Precursor Protein
- Multiple isoforms of APP exist, for example APP 695 , APP 751 , and APP 770 . Amino acids within APP are assigned numbers according to the sequence of the APP 770 isoform (see e.g., GenBank Accession No. P05067).
- Examples of specific isotypes of APP which are currently known to exist in humans are the 695 amino acid polypeptide described by Kang et. al. (1987) Nature 325:733-736 which is designated as the “normal” APP; the 751 amino acid polypeptide described by Ponte et al. (1988) Nature 331:525-527 (1988) and Tanzi et al. (1988) Nature 331:528-530; and the 770-amino acid polypeptide described by Kitaguchi et. al. (1988) Nature 331:530-532.
- a ⁇ is found in both a “short form”, 40 amino acids in length, and a “long form”, ranging from 42-43 amino acids in length.
- the short form, A ⁇ 40 consists of residues 672-711 of APP.
- the long form, e.g., A ⁇ 42 or A ⁇ 43 consists of residues 672-713 or 672-714, respectively.
- Part of the hydrophobic domain of APP is found at the carboxy end of A ⁇ , and may account for the ability of A ⁇ to aggregate, particularly in the case of the long form.
- a ⁇ peptide can be found in, or purified from, the body fluids of humans and other mammals, e.g. cerebrospinal fluid, including both normal individuals and individuals suffering from amyloidogenic disorders.
- ⁇ -amyloid protein include peptides resulting from secretase cleavage of APP and synthetic peptides having the same or essentially the same sequence as the cleavage products.
- a ⁇ peptides of the invention can be derived from a variety of sources, for example, tissues, cell lines, or body fluids (e.g. sera or cerebrospinal fluid).
- an A ⁇ can be derived from APP-expressing cells such as Chinese hamster ovary (CHO) cells stably transfected with APP 717V ⁇ F , as described, for example, in Walsh et al., (2002), Nature, 416, pp 535-539.
- An A ⁇ preparation can be derived from tissue sources using methods previously described (see, e.g., Johnson-Wood et al., (1997), Proc. Natl. Acad. Sci. USA 94:1550).
- a ⁇ peptides can be synthesized using methods which are well known to those in the art. See, for example, Fields et al., Synthetic Peptides: A User's Guide, ed.
- peptides can be synthesized using the automated Merrifield techniques of solid phase synthesis with the ⁇ -amino group protected by either t-Boc or F-moc chemistry using side chain protected amino acids on, for example, an Applied Biosystems Peptide Synthesizer Model 430A or 431. Longer peptide antigens can be synthesized using well known recombinant DNA techniques.
- a polynucleotide encoding the peptide or fusion peptide can be synthesized or molecularly cloned and inserted in a suitable expression vector for the transfection and heterologous expression by a suitable host cell.
- a ⁇ peptide also refers to related A ⁇ sequences that results from mutations in the A ⁇ region of the normal gene.
- soluble A ⁇ or “dissociated A ⁇ ” refers to non-aggregating or disaggregated A ⁇ polypeptide, including monomeric soluble as well as oligomeric soluble A ⁇ polypeptide (e.g., soluble A ⁇ dimers, trimers, and the like).
- Soluble A ⁇ can be found in vivo in biological fluids such as cerebrospinal fluid and/or serum. Soluble A ⁇ can also be prepared in vitro, e.g., by solubilizing A ⁇ peptide in appropriate solvents and/or solutions. For example, soluble A ⁇ can be prepared by dissolving lyophilized peptide in alcohol, e.g., HFIP followed by dilution into cold aqueous solution.
- soluble A ⁇ can be prepared by dissolving lyophilized peptide in neat DMSO with sonication. The resulting solution can be centrifuged (e.g., at 14,000 ⁇ g, 4° C., 10 minutes) to remove any insoluble particulates.
- insoluble A ⁇ or “aggregated A ⁇ ” refers to aggregated A ⁇ polypeptide, for example, A ⁇ held together by noncovalent bonds and which can occur in the fibrillary, toxic, ⁇ -sheet form of A ⁇ peptide that is found in neuritic plaques and cerebral blood vessels of patients with AD.
- a ⁇ e.g., A ⁇ 42
- a ⁇ is believed to aggregate, at least in part, due to the presence of hydrophobic residues at the C-terminus of the peptide (part of the transmembrane domain of APP).
- neuroactive A ⁇ species refers to an A ⁇ species (e.g., an A ⁇ peptide or form of A ⁇ peptide) that effects at least one activity or physical characteristic of a neuronal cell.
- Neuroactive A ⁇ species effect, for example, the function, biological activity, viability, morphology and/or architecture of a neuronal cell.
- the effect on neuronal cells can be cellular, for example, effecting the long-term-potentiation (LPT) of a neuronal cell or viability of a neuronal cell (neurotoxicity).
- LPT long-term-potentiation
- the effect can be on an in vivo neuronal system, for example, effecting a behavioral outcome in an appropriate animal test (e.g., a cognitive test).
- neutralize as used herein means to make neutral, counteract or make ineffective an activity or effect.
- neurodegenerative disease refers broadly to disorders or diseases associated with or characterized by degeneration of neurons and/or nervous tissues, e.g. an amyloidogenic disease.
- amyloidogenic disease or “amyloidogenic disorder” includes any disease associated with (or caused by) the formation or deposition of insoluble amyloid fibrils.
- exemplary amyloidogenic diseases include, but are not limited to systemic amyloidosis, Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), mature onset diabetes, Parkinson's disease, Huntington's disease, fronto-temporal dementia, and the prion-related transmissible spongiform encephalopathies (kuru and Creutzfeldt-Jacob disease in humans and scrapie and BSE in sheep and cattle, respectively).
- AD Alzheimer's disease
- CAA cerebral amyloid angiopathy
- mature onset diabetes Parkinson's disease
- Huntington's disease Huntington's disease
- fronto-temporal dementia fronto-temporal dementia
- prion-related transmissible spongiform encephalopathies kuru and Creutzfeldt-Jacob disease in humans and scrapie and BSE in sheep
- ⁇ -amyloid protein e.g., wild-type, variant, or truncated ⁇ -amyloid protein
- ⁇ -amyloid protein is the principal polypeptide component of the amyloid deposit.
- Alzheimer's disease is an example of a “disease characterized by deposits of A ⁇ ” or a “disease associated with deposits of A ⁇ ”, e.g., in the brain of a subject or patient.
- Other diseases characterized by deposits of A ⁇ can include uncharacterized diseases where amyloidogenic deposits are found in one or more regions of the brain associated with learning and/or memory, e.g., the hippocampus, amygdala, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- the hippocampus e.g., the hippocampus, amygdala, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- cognition refers to cognitive mental processes performed by a subject including, but not limited to, learning or memory (e.g., short-term or long term learning or memory), knowledge, awareness, attention and concentration, judgement, visual recognition, abstract thinking, executive functions, language, visual-spatial (i.e., visuo-spatial orientation) skills, visual recognition, balance/agility and sensorimotor activity.
- learning or memory e.g., short-term or long term learning or memory
- knowledge e.g., awareness, attention and concentration
- judgement visual recognition
- abstract thinking e.g., executive functions
- language e.g., visual-spatial skills
- visual recognition i.e., balance/agility and sensorimotor activity.
- Exemplary cognitive processes include learning and memory.
- cognitive disorder refers to a deficiency or impairment in one or more cognitive mental processes of a subject.
- Cognitive deficits may have a number of origins: a functional mechanism (anxiety, depression), physiological aging (age-associated memory impairment), brain injury, psychiatric disorders (e.g. schizophrenia), drugs, infections, toxicants, or anatomical lesions.
- exemplary cognitive deficits include deficiency or impairment in learning or memory (e.g., in short-term or long term learning and/or memory loss of intellectual abilities, judgment, language, motor skills, and/or abstract thinking).
- a ⁇ -related cognitive disorder refers to a cognitive disorder associated with, or characterized by, the development or presence of an A ⁇ peptide.
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of soluble A ⁇ .
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of insoluble A ⁇ .
- the A ⁇ -related disease or disorder is associated with or characterized by the presence of a neuroactive A ⁇ species (NA ⁇ ).
- NA ⁇ neuroactive A ⁇ species
- dementia disorder refers to a disorder characterized by dementia (i.e., general deterioration or progressive decline of cognitive abilities or dementia-like symptoms).
- Dementia disorders are often associated with, or caused by, one or more aberrant processes in the brain or central nervous system (e.g. neurodegeneration). Dementia disorders commonly progress from mild through severe stages and interfere with the ability of a subject to function independently in everyday life. Dementia may be classified as cortical or subcortical depending on the area of the brain affected. Dementia disorders do not include disorders characterized by a loss of consciousness (as in delirium) or depression, or other functional mental disorders (pseudodementia).
- Dementia disorders include the irreversible dementias such Alzheimer's disease, vascular dementia, Lewy body dementia, Jakob-Creutzfeldt disease, Pick's disease, progressive supranuclear palsy, Frontal lobe dementia, idiopathic basal ganglia calcification, Huntington disease, multiple sclerosis, and Parkinson's disease, as well as reversible dementias due to trauma (posttraumatic encephalopathy), intracranial tumors (primary or metastatic), subdural hematomas, metabolic and endocrinologic conditions (hypo- and hyperthyroidism, Wilson's disease, uremic encephalopathy, dialysis dementia, anoxic and post-anoxic dementia, and chronic electrolyte disturbances), deficiency states (Vitamin B12 deficiency and pellagra (vitamin B6)), infections (AIDS, syphilitic meningoencephalitis, limbic encephalitis, progressive multifocal leukoencephalopathy, fun
- a ⁇ -related dementia disorder refers to a dementia disorder associated with, or characterized by, the development or presence of an A ⁇ peptide.
- the phrase “improvement in cognition” refers to an enhancement or increase in a cognitive skill or function.
- the phrase “improving cognition” refers to the enhancing or increasing of a cognitive skill or function.
- An improvement in cognition is relative, for example, to cognition in the subject before a treatment according to the instant invention. Preferably, the improvement in cognition trends towards that of a normal subject or towards a standard or expected level.
- rapid improvement in cognition means taking a relatively or comparatively short time or occurring within a comparatively short time interval; i.e., that an effect (e.g., improvement) is accomplished, observed or achieved comparatively quickly, in terms of clinical relevance (i.e., as understood by a skilled clinician).
- An exemplary “rapid improvement in cognition” is accomplished, observed or achieved within one day (i.e., within 24 hours).
- a “rapid improvement in cognition” may be accomplished, observed or achieved in less than one day (i.e., less than 24 hours), for example, within 23, 22, 21, 20, 29, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour(s).
- a “rapid improvement in cognition” may alternatively be accomplished, observed or achieved in more than one day but preferably within one month, for example, within 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 days.
- Exemplary time intervals for accomplishing, observing or achieving a rapid improvement in cognition are within weeks, e.g., within three weeks, within two weeks or within one week or within, for example, 120 hours, 96 hours, 72 hours, 48 hours, 24 hours, 18 hours, 12 hours and/or 6 hours.
- the term “prolonged”, as used, for example, in the phrase “prolonged improvement in cognition” means occurring over a comparatively or relatively longer time interval than a suitable control; i.e., that a desired effect (e.g., improvement) occurs or is observed to be sustained without interruption for an extended or protracted time period, in terms of clinical relevance (i.e., as understood by a skilled clinician).
- An exemplary “prolonged improvement in cognition” is accomplished, observed or achieved for at least one week.
- a “prolonged improvement in cognition” may be accomplished, observed or achieved for more than one day (i.e., more than 24 hours), for example, for more than 36 hours, 48 hours (i.e., 2 days), 72 hours (i.e., 3 days), 96 hours (i.e., 4 days) 108 hours (i.e., 5 days) or 132 hours (i.e., 6 days).
- a “prolonged improvement in cognition” may alternatively be accomplished, observed or achieved for more than one week, e.g., for 8, 9, 10, 11, 12, 13, or 14 days (i.e., two weeks), three weeks, four weeks, five weeks, six weeks, or more. Exemplary time intervals over which a prolonged improvement in cognition is accomplished, observed or achieved include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days.
- modulation refers to both upregulation, i.e. stimulation, and downregulation, i.e. suppression, of a response.
- treatment is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease.
- an effective dose or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve the desired effect.
- therapeutically effective dose is defined as an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Amounts effective for this use will depend upon the severity of the disease, the patient's general physiology. e.g., the patient's body mass, age, gender, the route of administration, and other factors well known to physicians and/or pharmacologists.
- Effective doses may be expressed, for example, as the total mass of antibody (e.g., in grams, milligrams or micrograms) or as a ratio of mass of antibody to body mass (e.g., as grams per kilogram (g/kg), milligrams per kilogram (mg/kg), or micrograms per kilogram ( ⁇ g/kg).
- An effective dose of antibody used in the present methods will range, for example, between 1 ⁇ g/kg and 500 mg/kg.
- An exemplary range for effective doses of antibodies used in the methods of the present invention is between 0.1 mg/kg and 100 mg/kg.
- Exemplary effective doses include, but are not limited to, 10 ⁇ g/kg, 30 ⁇ g/kg, 100 ⁇ g/kg, 300 ⁇ g/kg, 1 mg/kg, 30 mg/kg and 100 mg/kg.
- administering refers to the act of introducing a pharmaceutical agent into a subject's body.
- An exemplary route of administration in the parenteral route e.g., subcutaneous, intravenous or intraperitoneal administration.
- patient includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment with one or more agents (e.g., immunotherapeutic agents) of the invention. Exemplary patients receive either prophylactic or therapeutic treatment with the immunotherapeutic agents of the invention.
- agents e.g., immunotherapeutic agents
- animal model or “model animal”, as used herein, includes a member of a mammalian species such as rodents, non-human primates, sheep, dogs, and cows that exhibit features or characteristics of a certain system of disease or disorder, e.g., a human system, disease or disorder.
- exemplary non-human animals selected from the rodent family include rabbits, guinea pigs, rats and mice, most preferably mice.
- An “animal model” of, or “model animal” having, a dementia disorder exhibits, for example, prominent cognitive deficits associated with a dementia-related disorder (e.g., AD).
- the model animal Preferably the model animal exhibits a progressive worsening of the cognitive deficit with increasing age, such that the disease progression in the model animal parallels the disease progression in a subject suffering from the dementia disorder.
- immunological reagent refers to an agent that comprises or consists of one or more immunoglobulins, antibodies, antibody fragments or antibody chains, as defined herein, or combinations thereof.
- immunological agent also includes nucleic acids encoding immunoglobulins, antibodies, antibody fragments, or antibody chains. Such nucleic acids can be DNA or RNA.
- a nucleic acid encoding an immunoglobulin is typically linked to regulatory elements, such as a promoter and enhancer, that allow expression of the nucleic acid in an appropriate cell or tissue.
- 12A11 immunological reagent refers to an immunological reagent having one or more characteristics of the monoclonal antibody 12A11, as described herein. Characteristics of the 12A11 monoclonal antibody include, without limitation, specific binding to A ⁇ peptide, preferential binding for soluble oligomeric A ⁇ , the ability to reduce plaque burden associated with amyloidogenic disorders in a subject and improve cognition in an animal model of AD. In certain aspects, 12A11 immunological reagents have conserved structural features with the 12A11 monoclonal antibody, for example, conserved antigen binding domains or regions (e.g., one or more 12A11 CDRs) as described herein.
- Exemplary 12A11 immunological reagents include 12A11 antibodies, humanized 12A11 antibodies, chimeric 12A11 antibodies, single-chain 12A11 antibodies, bispecific 12A11 antibodies, 12A11 antibody fragments, 12A11 antibody chains, variants thereof (e.g. affinity matured 12A11 antibody variants and 12A11 Fc antibody variants), or combinations thereof.
- the term 12A11 immunological reagent also includes any antibody (e.g. humanized antibody, chimeric antibody, single-chain antibody, bispecific antibody), antibody fragment, or antibody chain comprising at least one domain, region, or fragment derived from a 12A11 antibody, 12A11 antibody fragment, or 12A11 antibody chain.
- immunotherapeutic reagent refers to an immunological reagent suitable for therapeutic use.
- immunoglobulin or “antibody” (used interchangeably herein) refers to a protein having a basic four-polypeptide chain structure consisting of two heavy and two light chains, said chains being stabilized, for example, by interchain disulfide bonds, which has the ability to specifically bind antigen. It is intended that the term “antibody” encompass any Ig class or any Ig subclass (e.g.
- IgG1, IgG2, IgG3, and IgG4 subclasses of IgG obtained from any source (e.g., in exemplary embodiments, humans and non-human primates, and in additional embodiments, rodents, lagomorphs, caprines, bovines, equines, ovines, etc.).
- Ig class or “immunoglobulin class”, as used herein, refers to the five classes of immunoglobulin that have been identified in humans and higher mammals, IgG, IgM, IgA, IgD, and IgE.
- Ig subclass refers to the two subclasses of IgM (H and L), three subclasses of IgA (IgA1, IgA2, and secretory IgA), and four subclasses of IgG (IgG 1 , IgG 2 , IgG 3 , and IgG 4 ) that have been identified in humans and higher mammals.
- IgG subclass refers to the four subclasses of immunoglobulin class IgG-IgG 1 , IgG 2 , IgG3, and IgG 4 that have been identified in humans and higher mammals by the ⁇ heavy chains of the immunoglobulins, ⁇ 1 - ⁇ 4 , respectively.
- single-chain immunoglobulin or “single-chain antibody” (used interchangeably herein) refers to a protein having a two-polypeptide chain structure consisting of a heavy and a light chain, said chains being stabilized, for example, by interchain peptide linkers, which has the ability to specifically bind antigen.
- domain refers to a globular region of a heavy or light chain polypeptide comprising peptide loops (e.g., comprising 3 to 4 peptide loops) stabilized, for example, by ⁇ -pleated sheet and/or intrachain disulfide bond. Domains are further referred to herein as “constant” or “variable”, based on the relative lack of sequence variation within the domains of various class members in the case of a “constant” domain, or the significant variation within the domains of various class members in the case of a “variable” domain.
- Antibody or polypeptide “domains” are often referred to interchangeably in the art as antibody or polypeptide “regions”.
- the “constant” domains of an antibody light chain are referred to interchangeably as “light chain constant regions”, “light chain constant domains”, “CL” regions or “CL” domains.
- the “constant” domains of an antibody heavy chain are referred to interchangeably as “heavy chain constant regions”, “heavy chain constant domains”, “CH” regions or “CH” domains).
- the “variable” domains of an antibody light chain are referred to interchangeably as “light chain variable regions”, “light chain variable domains”, “VL” regions or “VL” domains).
- the “variable” domains of an antibody heavy chain are referred to interchangeably as “heavy chain constant regions”, “heavy chain constant domains”, “VH” regions or “VH” domains).
- region can also refer to a part or portion of an antibody chain or antibody chain domain (e.g., a part or portion of a heavy or light chain or a part or portion of a constant or variable domain, as defined herein), as well as more discrete parts or portions of said chains or domains.
- light and heavy chains or light and heavy chain variable domains include “complementarity determining regions” or “CDRs” interspersed among “framework regions” or “FRs”, as defined herein.
- an antigen binding site refers to a site that specifically binds (immunoreacts with) an antigen (e.g., a cell surface or soluble antigen).
- Antibodies of the invention preferably comprise at least two antigen binding sites.
- An antigen binding site commonly includes immunoglobulin heavy chain and light chain CDRs and the binding site formed by these CDRs determines the specificity of the antibody.
- An “antigen binding region” or “antigen binding domain” is a region or domain (e.g., an antibody region or domain that includes an antibody binding site as defined supra.
- Immunoglobulins or antibodies can exist in monomeric or polymeric form, for example, IgM antibodies which exist in pentameric form and/or IgA antibodies which exist in monomeric, dimeric or multimeric form.
- fragment refers to a part or portion of an antibody or antibody chain comprising fewer amino acid residues than an intact or complete antibody or antibody chain. Fragments can be obtained via chemical or enzymatic treatment of an intact or complete antibody or antibody chain. Fragments can also be obtained by recombinant means. Exemplary fragments include Fab, Fab′, F(ab′)2, Fabc and/or Fv fragments.
- antigen-binding fragment refers to a polypeptide fragment of an immunoglobulin or antibody that binds antigen or competes with intact antibody (i.e., with the intact antibody from which they were derived) for antigen binding (i.e., specific binding). Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins. Binding fragments include Fab, Fab′, F(ab′) 2 , Fabc, Fv, single chains, and single chain antibodies. Other than “bispecific” or “bifunctional” immunoglobulins or antibodies, an immunoglobulin or antibody is understood to have each of its antigen-binding sites identical.
- bispecific or “bifunctional antibody” is an artificial hybrid antibody having two different heavy/light chain pairs and two different antigen-binding sites.
- Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab′ fragments. See, e.g., Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al., J. Immunol. 148, 1547-1553 (1992).
- the term “monoclonal antibody” refers to an antibody derived from a clonal population of antibody-producing cells (e.g., B lymphocytes or B cells) which is homogeneous in structure and antigen specificity.
- the term “polyclonal antibody” refers to a plurality of antibodies originating from different clonal populations of antibody-producing cells which are heterogeneous in their structure and epitope specificity but which recognize a common antigen.
- Monoclonal and polyclonal antibodies may exist within bodily fluids, as crude preparations, or may be purified, as described herein.
- humanized immunoglobulin refers to an immunoglobulin or antibody that includes at least one humanized immunoglobulin or antibody chain (i.e., at least one humanized light or heavy chain).
- humanized immunoglobulin chain or “humanized antibody chain” (i.e., a “humanized immunoglobulin light chain” or “humanized immunoglobulin heavy chain”) refers to a immunoglobulin or antibody chain (i.e., a light or heavy chain, respectively) having a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) (e.g., at least one CDR, preferably two CDRs, more preferably three CDRs) substantially from a non-human immunoglobulin or antibody, and further includes constant regions (e.g., at least one constant region or portion thereof, in the case of a light chain, and preferably three constant regions in the case of a heavy chain).
- CDRs complementarity determining regions
- humanized variable region refers to a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) substantially from a non-human immunoglobulin or antibody.
- CDRs complementarity determining regions
- a “humanized immunoglobulin” or “humanized antibody” encompassed by this disclosure can be made using any of the methods described herein or those that are well known in the art.
- substantially from a human immunoglobulin or antibody or “substantially human” means that, when aligned to a human immunoglobulin or antibody amino sequence for comparison purposes, the region shares at least 80-90%, 90-95%, or 95-99% identity (i.e., local sequence identity) with the human framework or constant region sequence, allowing, for example, for conservative substitutions, consensus sequence substitutions, germline substitutions, backmutations, and the like.
- conservative substitutions, consensus sequence substitutions, germline substitutions, backmutations, and the like is often referred to as “optimization” of a humanized antibody or chain.
- substantially from a non-human immunoglobulin or antibody or “substantially non-human” means having an immunoglobulin or antibody sequence at least 80-95%, preferably at least 90-95%, more preferably, 96%, 97%, 98%, or 99% identical to that of a non-human organism, e.g., a non-human mammal.
- corresponding region refers to a region or residue on a second amino acid or nucleotide sequence which occupies the same (i.e., equivalent) position as a region or residue on a first amino acid or nucleotide sequence, when the first and second sequences are optimally aligned for comparison purposes.
- significant identity means that two polypeptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 50-60% sequence identity, preferably at least 60-70% sequence identity, more preferably at least 70-80% sequence identity, more preferably at least 80-90% identity, even more preferably at least 90-95% identity, and even more preferably at least 95% sequence identity or more (e.g., 99% sequence identity or more).
- substantially identical means that two polypeptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80-90% sequence identity, preferably at least 90-95% sequence identity, and more preferably at least 95% sequence identity or more (e.g., 99% sequence identity or more).
- sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
- test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
- Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., Current Protocols in Molecular Biology).
- BLAST algorithm One example of algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403 (1990).
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (publicly accessible through the National Institutes of Health NCBI internet server).
- default program parameters can be used to perform the sequence comparison, although customized parameters can also be used.
- W wordlength
- E expectation
- BLOSUM62 scoring matrix see Henikoff& Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).
- residue positions which are not identical differ by conservative amino acid substitutions.
- amino acids are grouped as follows: Group I (hydrophobic sidechains): leu, met, ala, val, leu, ile; Group II (neutral hydrophilic side chains): cys, ser, thr; Group III (acidic side chains): asp, glu; Group IV (basic side chains): asn, gln, his, lys, arg; Group V (residues influencing chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe.
- Conservative substitutions involve substitutions between amino acids in the same class. Non-conservative substitutions constitute exchanging a member of one of these classes for a member of another.
- humanized immunoglobulins or antibodies bind antigen with an affinity that is within a factor of three, four, or five of that of the corresponding non-humanized antibody.
- the nonhumanized antibody has a binding affinity of 10 9 M ⁇ 1
- humanized antibodies will have a binding affinity of at least 3 ⁇ 10 9 M ⁇ , 4 ⁇ 10 9 M ⁇ 1 or 5 ⁇ 10 9 M ⁇ 1 .
- direct antigen e.g., A ⁇
- a chain is said to “direct antigen binding” when it confers upon an intact immunoglobulin or antibody (or antigen binding fragment thereof) a specific binding property or binding affinity.
- a mutation e.g., a backmutation
- a mutation is said to substantially affect the ability of a heavy or light chain to direct antigen binding if it affects (e.g., decreases) the binding affinity of an intact immunoglobulin or antibody (or antigen binding fragment thereof) comprising said chain by at least an order of magnitude compared to that of the antibody (or antigen binding fragment thereof) comprising an equivalent chain lacking said mutation.
- a mutation “does not substantially affect (e.g., decrease) the ability of a chain to direct antigen binding” if it affects (e.g., decreases) the binding affinity of an intact immunoglobulin or antibody (or antigen binding fragment thereof) comprising said chain by only a factor of two, three, or four of that of the antibody (or antigen binding fragment thereof) comprising an equivalent chain lacking said mutation.
- chimeric immunoglobulin refers to an immunoglobulin or antibody whose variable regions derive from a first species and whose constant regions derive from a second species. Chimeric immunoglobulins or antibodies can be constructed, for example by genetic engineering, from immunoglobulin gene segments belonging to different species.
- humanized immunoglobulin or “humanized antibody” are not intended to encompass chimeric immunoglobulins or antibodies, as defined infra.
- humanized immunoglobulins or antibodies are chimeric in their construction (i.e., comprise regions from more than one species of protein), they include additional features (i.e., variable regions comprising donor CDR residues and acceptor framework residues) not found in chimeric immunoglobulins or antibodies, as defined herein.
- formation refers to the tertiary structure of a protein or polypeptide (e.g., an antibody, antibody chain, domain or region thereof).
- light (or heavy) chain conformation refers to the tertiary structure of a light (or heavy) chain variable region
- antibody conformation or “antibody fragment conformation” refers to the tertiary structure of an antibody or fragment thereof.
- “Specific binding” of an antibody means that the antibody exhibits appreciable affinity for a particular antigen or epitope and, generally, does not exhibit significant crossreactivity. In exemplary embodiments, the antibody exhibits no crossreactivity (e.g., does not crossreact with non-A ⁇ peptides or with remote epitopes on A ⁇ ).
- “Appreciable” or preferred binding includes binding with an affinity of at least 10 6 , 10 7 , 10 8 , 10 9 M ⁇ 1 , or 10 10 M ⁇ 1 . Affinities greater than 10 7 M ⁇ 1 , preferably greater than 10 8 M ⁇ 1 are more preferred.
- a preferred binding affinity can be indicated as a range of affinities, for example, 10 6 to 10 10 M ⁇ 1 , preferably 10 7 to 10 10 M ⁇ 1 , more preferably 10 8 to 10 10 M ⁇ 1 .
- An antibody that “does not exhibit significant crossreactivity” is one that will not appreciably bind to an undesirable entity (e.g., an undesirable proteinaceous entity).
- an antibody that specifically binds to A ⁇ will appreciably bind A ⁇ but will not significantly react with non-A ⁇ proteins or peptides (e.g., non-A ⁇ proteins or peptides included in plaques).
- an antibody specific for a particular epitope will, for example, not significantly crossreact with remote epitopes on the same protein or peptide.
- Specific binding can be determined according to any art-recognized means for determining such binding. Preferably, specific binding is determined according to Scatchard analysis and/or competitive binding assays.
- affinity refers to the strength of the binding of a single antigen-combining site with an antigenic determinant. Affinity depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, on the distribution of charged and hydrophobic groups, etc.
- Antibody affinity can be measured by equilibrium dialysis or by the kinetic BIACORETM method.
- the BIACORETM method relies on the phenomenon of surface plasmon resonance (SPR), which occurs when surface plasmon waves are excited at a metal/liquid interface. Light is directed at, and reflected from, the side of the surface not in contact with sample, and SPR causes a reduction in the reflected light intensity at a specific combination of angle and wavelength. Bimolecular binding events cause changes in the refractive index at the surface layer, which are detected as changes in the SPR signal.
- SPR surface plasmon resonance
- the dissociation constant, KD, and the association constant, KA are quantitative measures of affinity.
- free antigen (Ag) and free antibody (Ab) are in equilibrium with antigen-antibody complex (Ag ⁇ Ab), and the rate constants, ka and kd, quantitate the rates of the individual reactions:
- KD dissociation constant
- KD dissociation constant
- KD has units of concentration, most typically M, mM, ⁇ M, nM, pM, etc.
- KA has units of inverse concentration, most typically M ⁇ 1 , mM ⁇ 1 , ⁇ M ⁇ 1 , nM ⁇ 1 , pM ⁇ 1 , etc.
- vidity refers to the strength of the antigen-antibody bond after formation of reversible complexes.
- Fc immunoglobulin variant or “Fc antibody variant” includes immunoglobulins or antibodies (e.g., humanized immunoglobulins, chimeric immunoglobulins, single chain antibodies, antibody fragments, etc.) having an altered Fc region. Fc regions can be altered, for example, such that the immunoglobulin has an altered effector function.
- An amino acid alteration includes an amino acid substitution, addition, deletion and/or modification of one or more amino acids of an immunoglobulin, for example, in the Fc region of the immunoglobulin.
- immunoglobulins of the invention include one or more mutations in the Fc region.
- the Fc region includes one or more amino acid alterations in the hinge region, for example, at EU positions 234, 235, 236 and/or 237.
- Antibodies including hinge region mutations at one or more of amino acid positions 234, 235, 236 and/or 237 can be made, as described in, for example, U.S. Pat. No. 5,624,821, and U.S. Pat. No. 5,648,260, incorporated by reference herein.
- effector function refers to an activity that resides in the Fc region of an antibody (e.g., an IgG antibody) and includes, for example, the ability of the antibody to bind effector molecules such as complement and/or Fc receptors, which can control several immune functions of the antibody such as effector cell activity, lysis, complement-mediated activity, antibody clearance, and antibody half-life.
- effector molecule refers to a molecule that is capable of binding to the Fc region of an antibody (e.g., an IgG antibody) including, but not limited to, a complement protein or a Fc receptor.
- effector cell refers to a cell capable of binding to the Fc portion of an antibody (e.g., an IgG antibody) typically via an Fc receptor expressed on the surface of the effector cell including, but not limited to, lymphocytes, e.g., antigen presenting cells and T cells.
- an antibody e.g., an IgG antibody
- Fc receptor expressed on the surface of the effector cell including, but not limited to, lymphocytes, e.g., antigen presenting cells and T cells.
- Fc region refers to a C-terminal region of an IgG antibody, in particular, the C-terminal region of the heavy chain(s) of said IgG antibody. Although the boundaries of the Fc region of an IgG heavy chain can vary slightly, a Fc region is typically defined as spanning from about amino acid residue Cys226 to the carboxyl-terminus of a human IgG heavy chain(s).
- aglycosylated antibody refers to an antibody lacking one or more carbohydrates by virtue of a chemical or enzymatic process, mutation of one or more glycosylation sites, expression in bacteria, etc.
- An aglycosylated antibody may be a deglycosylated antibody, that is an antibody for which the Fc carbohydrate has been removed, for example, chemically or enzymatically.
- the aglycosylated antibody may be a nonglycosylated or unglycosylated antibody, that is an antibody that was expressed without Fc carbohydrate, for example by mutation of one or more residues that encode the glycosylation pattern or by expression in an organism that does not attach carbohydrates to proteins, for example bacteria.
- Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)
- EU numbering is also taught in Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)) and, for example, refers to the numbering of the residues in heavy chain antibody sequences using the EU index as described therein. This numbering system is based on the sequence of the Eu antibody described in Edelman et al., 63(1):78-85 (1969).
- Fc receptor refers to a receptor that binds to the Fc region of an antibody.
- Typical Fc receptors which bind to an Fc region of an antibody include, but are not limited to, receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
- Other Fc receptors include the neonatal Fc receptors (FcRn) which regulate antibody half-life. Fc receptors are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995).
- an “antigen” is an entity (e.g., a proteinaceous entity or peptide) to which an immunoglobulin or antibody (or antigen-binding fragment thereof) specifically binds.
- epitopes refers to a site on an antigen to which an immunoglobulin or antibody (or antigen binding fragment thereof) specifically binds.
- Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
- An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation.
- Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology , Vol. 66, G. E. Morris, Ed. (1996).
- Antibodies that recognize the same epitope can be identified in a simple immunoassay showing the ability of one antibody to block the binding of another antibody to a target antigen, i.e., a competitive binding assay.
- Competitive binding is determined in an assay in which the immunoglobulin under test inhibits specific binding of a reference antibody to a common antigen, such as A ⁇ .
- Numerous types of competitive binding assays are known, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli et al., Methods in Enzymology 9:242 (1983)); solid phase direct biotin-avidin EIA (see Kirkland et al., J.
- such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabeled test immunoglobulin and a labeled reference immunoglobulin.
- Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin.
- the test immunoglobulin is present in excess.
- a competing antibody when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 50-55%, 55-60%, 60-65%, 65-70% 70-75% or more.
- An epitope is also recognized by immunologic cells, for example, B cells and/or T cells.
- Cellular recognition of an epitope can be determined by in vitro assays that measure antigen-dependent proliferation, as determined by 3 H-thymidine incorporation, by cytokine secretion, by antibody secretion, or by antigen-dependent killing (cytotoxic T lymphocyte assay).
- Exemplary epitopes or antigenic determinants to which an antibody of the invention binds can be found within the human amyloid precursor protein (APP), but are preferably found within the A ⁇ peptide of APP.
- Exemplary epitopes or antigenic determinants within A ⁇ , as described herein, are located within the N-terminus, central region, or C-terminus of A ⁇ .
- N-terminal epitope is an epitope or antigenic determinant comprising residues located within the N-terminus of A ⁇ peptide.
- Exemplary N-terminal epitopes include residues within amino acids 1-10 or 1-12 of A ⁇ , preferably from residues 1-3, 14, 1-5, 1-6, 1-7, 2-6, 3-6, or 3-7 of A ⁇ 42.
- Other exemplary N-terminal epitopes start at residues 1-3 and end at residues 7-11 of A ⁇ .
- Additional exemplary N-terminal epitopes include residues 24, 5, 6, 7 or 8 of AD, residues 3-5, 6, 7, 8 or 9 of A ⁇ , or residues 4-7, 8, 9 or 10 of A ⁇ 42.
- Central epitopes are epitopes or antigenic determinants comprising residues located within the central or mid-portion of the A ⁇ peptide.
- Exemplary central epitopes include residues within amino acids 13-38, preferably within 16-21, 16-22, 16-23, 16-24, 18-21, 19-21, 19-22, 19-23 or 19-24 of the A ⁇ peptide.
- C-terminal epitopes are epitopes or antigenic determinants comprising residues located within the C-terminus of the A ⁇ peptide (e.g., within about amino acids 3040 or 30-42 of A ⁇ ). Additional exemplary epitopes or antigenic determinants include residues 33-40 or 33-42 of A ⁇ . Such epitopes can be referred to as “C-terminal epitopes”.
- an antibody When an antibody is said to bind to an epitope within specified residues, such as A ⁇ 3-7, what is meant is that the antibody specifically binds to a polypeptide containing the specified residues (i.e., A ⁇ 3-7 in this an example). Such an antibody does not necessarily contact every residue within A ⁇ 3-7. Nor does every single amino acid substitution or deletion within A ⁇ 3-7 necessarily significantly affect binding affinity.
- a ⁇ antibody and “anti-A ⁇ ” are used interchangeably herein to refer to an antibody that binds to one or more epitopes or antigenic determinants within A ⁇ protein.
- Exemplary A ⁇ antibodies include N-terminal A ⁇ antibodies, central A ⁇ antibodies, and C-terminal A ⁇ antibodies.
- N-terminal A ⁇ antibody shall refer to an A ⁇ antibody that recognizes at least one N-terminal epitope or antigenic determinant.
- central A ⁇ antibody shall refer to an A ⁇ antibody that recognizes at least one central epitope or antigenic determinant.
- C-terminal A ⁇ antibody shall refer to an A ⁇ antibody that recognizes at least one C-terminal epitope or antigenic determinant.
- immunological response is the development of a humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a subject.
- a humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a subject can be an active response induced by administration of immunogen or a passive response induced by administration of antibody or primed T-cells.
- a cellular immune response is elicited by the presentation of polypeptide epitopes in association with Class I or Class II MHC molecules to activate antigen-specific CD4 + T helper cells and/or CD8 + cytotoxic T cells.
- the response may also involve activation of monocytes, macrophages, natural killer (“NK”) cells, basophils, dendritic cells, astrocytes, microglia cells, eosinophils or other components of innate immunity.
- NK natural killer
- the presence of a cell-mediated immunological response can be determined by proliferation assays (CD4 + T cells) or CTL (cytotoxic T lymphocyte) assays (see Burke, REF; Tigges, REF).
- the relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating antibodies and T-cells from an immunized animal or individual and measuring protective or therapeutic effect in a second subject.
- immunotherapy refers to a treatment, for example, a therapeutic or prophylactic treatment, of a disease or disorder intended to and/or producing an immune response (e.g., an active or passive immune response).
- an immune response e.g., an active or passive immune response
- an “immunogenic agent” or “immunogen” is capable of inducing an immunological response against itself on administration to a patient, optionally in conjunction with an adjuvant.
- An “immunogenic composition” is one that comprises an immunogenic agent.
- adjuvant refers to a compound that when administered in conjunction with an antigen augments the immune response to the antigen, but when administered alone does not generate an immune response to the antigen.
- adjuvants can augment an immune response by several mechanisms including lymphocyte recruitment, stimulation of B and/or T cells, and stimulation of macrophages.
- the term “kit” is used in reference to a combination of reagents and other materials which facilitate sample analysis.
- the immunoassay kit of the present invention includes a suitable antigen, binding agent comprising a detectable moiety, and detection reagents.
- a system for amplifying the signal produced by detectable moieties may or may not also be included in the kit.
- the kit includes, but is not limited to, components such as apparatus for sample collection, sample tubes, holders, trays, racks, dishes, plates, instructions to the kit user, solutions or other chemical reagents, and samples to be used for standardization, normalization, and/or control samples.
- a “suitable control” or “appropriate control” is any control or standard familiar to one of ordinary skill in the art useful for comparison purposes.
- a “suitable control” or “appropriate control” is a value, level, feature, characteristic, property, etc. determined prior to performing a methodology of the invention, as described herein.
- a “suitable control” or “appropriate control” is a value, level, feature, characteristic, property, etc. determined in a subject, e.g., a control or normal subject exhibiting, for example, normal traits.
- a “suitable control” or “appropriate control” is a predefined value, level, feature, characteristic, property, etc.
- Immunological and therapeutic reagents of the invention comprise or consist of immunogens or antibodies, or functional or antigen binding fragments thereof, as defined herein.
- the basic antibody structural unit is known to comprise a tetramer of subunits. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
- the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- the carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
- Light chains are classified as either kappa or lambda and are about 230 residues in length.
- Heavy chains are classified as gamma ( ⁇ ), mu ( ⁇ ), alpha ( ⁇ ), delta ( ⁇ ), or epsilon ( ⁇ ), are about 450-600 residues in length, and define the antibody's isotype as IgG, IgM, IgA, IgD and IgE, respectively.
- Both heavy and light chains are folded into domains.
- domain refers to a globular region of a protein, for example, an immunoglobulin or antibody.
- Immunoglobulin or antibody domains include, for example, three or four peptide loops stabilized by ⁇ -pleated sheet and an interchain disulfide bond.
- Intact light chains have, for example, two domains (V L and C L ) and intact heavy chains have, for example, four or five domains (V H , C H 1, C H 2, and C H 3).
- variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids.
- variable regions of each light/heavy chain pair form the antibody binding site.
- an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
- the chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs.
- FR relatively conserved framework regions
- Naturally-occurring chains or recombinantly produced chains can be expressed with a leader sequence which is removed during cellular processing to produce a mature chain. Mature chains can also be recombinantly produced having a non-naturally occurring leader sequence, for example, to enhance secretion or alter the processing of a particular chain of interest.
- both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- FR4 also is referred to in the art as the D/J region of the variable heavy chain and the J region of the variable light chain. The assignment of amino acids to each domain is in accordance with the definitions of Kabat.
- Therapeutic agents of the invention include antibodies that specifically bind to A ⁇ or to other components of the amyloid plaque.
- Preferred antibodies are monoclonal antibodies. Some such antibodies bind specifically to the aggregated form of A ⁇ without binding to the soluble form. Some bind specifically to the soluble form without binding to the aggregated form. Some bind to both aggregated and soluble forms. Some antibodies bind A ⁇ in plaques. Some antibodies can cross the blood-brain barrier. Some antibodies can reduce amyloid burden in a subject. Some antibodies can reduce neuritic dystrophy in a subject. Some antibodies can maintain synaptic architecture (e.g., synaptophysin). Some antibodies can neutralize one or more neuroactive forms of A ⁇ .
- antibodies of the invention for use in passive immunotherapy bind soluble A ⁇ peptide including monomeric soluble and/or oligomeric soluble A ⁇ polypeptide (e.g., soluble A ⁇ dimers, trimers, and the like).
- the antibody is capable of binding aggregated or insoluble A ⁇ deposited in plaques to decrease the size or density of amyloid plaques.
- the antibody is capable of capturing soluble A ⁇ , including monomeric soluble as well as oligomeric soluble A ⁇ polypeptide (e.g., soluble A ⁇ dimers, trimers, and the like), and preventing accumulation of A ⁇ and/or promoting removal of A ⁇ from the CNS.
- the antibodies of the invention are capable of binding to both soluble and insoluble A ⁇ peptides or fragments thereof, and are capable of preventing the formation of additional amyloid plaque while also decreasing the size and density of existing amyloid plaques.
- Antibodies used in therapeutic methods preferably have an intact constant region or at least sufficient of the constant region to interact with an Fc receptor.
- Preferred antibodies are those efficacious at stimulating Fc-mediated phagocytosis of A ⁇ in plaques.
- Human isotype IgG1 is preferred because of it having highest affinity of human isotypes for the FcRI receptor on phagocytic cells (e.g., on brain resident macrophages or microglial cells).
- Human IgG1 is the equivalent of murine IgG2a, the latter thus suitable for testing in vivo efficacy in animal (e.g., mouse) models of Alzheimer's.
- Bispecific Fab fragments can also be used, in which one arm of the antibody has specificity for A ⁇ , and the other for an Fc receptor.
- Preferred antibodies bind to A ⁇ with a binding affinity greater than (or equal to) about 10 6 , 10 7 , 10 8 , 10 9 , or 10 10 M ⁇ 1 (including affinities intermediate of these
- Antibodies of the present invention also include those antibodies which are capable of binding and/or clearing soluble A ⁇ in the CNS or brain of a subject.
- Exemplary antibodies also include those antibodies which are capable of capturing soluble A ⁇ , e.g., in the bloodstream of a subject.
- Preferred antibodies are capable of rapidly improving cognition in a subject, e.g., via clearance and/or capture of soluble A ⁇ .
- Monoclonal antibodies bind to a specific epitope within A ⁇ that can be a conformational or nonconformational epitope. Prophylactic and therapeutic efficacy of antibodies can be tested using the transgenic animal model procedures described in the Examples.
- Preferred monoclonal antibodies bind to an epitope within residues 1-10 of AD (with the first N terminal residue of natural A ⁇ designated 1), more preferably to an epitope within residues 3-7 of A ⁇ .
- multiple monoclonal antibodies having binding specificities to different epitopes are used, for example, an antibody specific for an epitope within residues 3-7 of A ⁇ can be co-administered with an antibody specific for an epitope outside of residues 3-7 of A ⁇ .
- Such antibodies can be administered sequentially or simultaneously.
- Antibodies to amyloid components other than A ⁇ can also be used (e.g., administered or co-administered).
- Epitope specificity of an antibody can be determined, for example, by forming a phage display library in which different members display different subsequences of A ⁇ . The phage display library is then selected for members specifically binding to an antibody under test. A family of sequences is isolated. Typically, such a family contains a common core sequence, and varying lengths of flanking sequences in different members. The shortest core sequence showing specific binding to the antibody defines the epitope bound by the antibody. Antibodies can also be tested for epitope specificity in a competition assay with an antibody whose epitope specificity has already been determined.
- antibodies that compete with the 12A11 antibody for binding to A ⁇ bind to the same or similar epitope as 12A11, i.e., within residues A ⁇ 3-7. Screening antibodies for epitope specificity is a useful predictor of therapeutic efficacy. For example, an antibody determined to bind to an epitope within residues 1-7 of A ⁇ is likely to be effective in preventing and treating Alzheimer's disease according to the methodologies of the present invention.
- Antibodies that specifically bind to a preferred segment of A ⁇ without binding to other regions of A ⁇ have a number of advantages relative to monoclonal antibodies binding to other regions or polyclonal sera to intact A ⁇ .
- dosages of antibodies that specifically bind to preferred segments contain a higher molar dosage of antibodies effective in clearing amyloid plaques.
- antibodies specifically binding to preferred segments can induce a clearing response against amyloid deposits without inducing a clearing response against intact APP polypeptide, thereby reducing the potential side effects.
- the present invention features non-human antibodies, for example, antibodies having specificity for the preferred A ⁇ epitopes of the invention.
- Such antibodies can be used in formulating various therapeutic compositions of the invention or, preferably, provide complementarity determining regions for the production of humanized or chimeric antibodies (described in detail below).
- the production of non-human monoclonal antibodies e.g., murine, guinea pig, primate, rabbit or rat, can be accomplished by, for example, immunizing the animal with A ⁇ .
- a longer polypeptide comprising A ⁇ or an immunogenic fragment of A ⁇ or anti-idiotypic antibodies to an antibody to A ⁇ can also be used. See Harlow & Lane, supra, incorporated by reference for all purposes).
- an immunogen can be obtained from a natural source, by peptide synthesis or by recombinant expression.
- the immunogen can be administered fused or otherwise complexed with a carrier protein, as described below.
- the immunogen can be administered with an adjuvant.
- adjuvant refers to a compound that when administered in conjunction with an antigen augments the immune response to the antigen, but when administered alone does not generate an immune response to the antigen.
- Adjuvants can augment an immune response by several mechanisms including lymphocyte recruitment, stimulation of B and/or T cells, and stimulation of macrophages.
- adjuvants can be used as described below. Complete Freund's adjuvant followed by incomplete adjuvant is preferred for immunization of laboratory animals.
- Rabbits or guinea pigs are typically used for making polyclonal antibodies.
- Exemplary preparation of polyclonal antibodies, e.g., for passive protection, can be performed as follows. 125 non-transgenic mice are immunized with 100 ⁇ g A ⁇ 1-42, plus Complete/Incomplete Freund's Adjuvant (CFA/IFA adjuvant), and euthanized at 4-5 months. Blood is collected from immunized mice. IgG is separated from other blood components. Antibody specific for the immunogen may be partially purified by affinity chromatography. An average of about 0.5-1 mg of immunogen-specific antibody is obtained per mouse, giving a total of 60-120 mg.
- Mice are typically used for making monoclonal antibodies.
- Monoclonals can be prepared against a fragment by injecting the fragment or longer form of A ⁇ into a mouse, preparing hybridomas and screening the hybridomas for an antibody that specifically binds to A ⁇ .
- antibodies are screened for binding to a specific region or desired fragment of A ⁇ without binding to other nonoverlapping fragments of A ⁇ . The latter screening can be accomplished by determining binding of an antibody to a collection of deletion mutants of an A ⁇ peptide and determining which deletion mutants bind to the antibody. Binding can be assessed, for example, by Western blot or ELISA. The smallest fragment to show specific binding to the antibody defines the epitope of the antibody.
- epitope specificity can be determined by a competition assay is which a test and reference antibody compete for binding to A ⁇ . If the test and reference antibodies compete, then they bind to the same epitope or epitopes sufficiently proximal such that binding of one antibody interferes with binding of the other.
- the preferred isotype for such antibodies is mouse isotype IgG2a or equivalent isotype in other species.
- Mouse isotype IgG2a is the equivalent of human isotype IgG1 (e.g., human IgG1).
- the present invention also features chimeric and/or humanized antibodies (i.e., chimeric and/or humanized immunoglobulins) specific for beta amyloid peptide.
- Chimeric and/or humanized antibodies have the same or similar binding specificity and affinity as a mouse or other nonhuman antibody that provides the starting material for construction of a chimeric or humanized antibody.
- chimeric antibody refers to an antibody whose light and heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin gene segments belonging to different species.
- V variable
- C constant
- IgG1 and IgG4 Human isotypes IgG1 and IgG4 are exemplary.
- a typical chimeric antibody is thus a hybrid protein consisting of the V or antigen-binding domain from a mouse antibody and the C or effector domain from a human antibody.
- humanized antibody refers to an antibody comprising at least one chain comprising variable region framework residues substantially from a human antibody chain (referred to as the acceptor immunoglobulin or antibody) and at least one complementarity determining region substantially from a mouse antibody, (referred to as the donor immunoglobulin or antibody).
- acceptor immunoglobulin or antibody referred to as the acceptor immunoglobulin or antibody
- donor immunoglobulin or antibody referred to as the donor immunoglobulin or antibody.
- the substitution of mouse CDRs into a human variable domain framework is most likely to result in retention of their correct spatial orientation if the human variable domain framework adopts the same or similar conformation to the mouse variable framework from which the CDRs originated. This is achieved by obtaining the human variable domains from human antibodies whose framework sequences exhibit a high degree of sequence identity with the murine variable framework domains from which the CDRs were derived.
- the heavy and light chain variable framework regions can be derived from the same or different human antibody sequences.
- the human antibody sequences can be the sequences of naturally occurring human antibodies or can be consensus sequences of several human antibodies. See Kettleborough et al., Protein Engineering 4:773 (1991); Kolbinger et al., Protein Engineering 6:971 (1993) and Carter et al., WO 92/22653.
- the next step is to determine which, if any, residues from these components should be substituted to optimize the properties of the resulting humanized antibody.
- substitution of human amino acid residues with murine should be minimized, because introduction of murine residues increases the risk of the antibody eliciting a human-anti-mouse-antibody (HAMA) response in humans.
- HAMA human-anti-mouse-antibody
- Art-recognized methods of determining immune response can be performed to monitor a HAMA response in a particular patient or during clinical trials. Patients administered humanized antibodies can be given an immunogenicity assessment at the beginning and throughout the administration of said therapy.
- the HAMA response is measured, for example, by detecting antibodies to the humanized therapeutic reagent, in serum samples from the patient using a method known to one in the art, including surface plasmon resonance technology (BIACORE) and/or solid-phase ELISA analysis.
- BIACORE surface plasmon resonance technology
- Certain amino acids from the human variable region framework residues are selected for substitution based on their possible influence on CDR conformation and/or binding to antigen.
- the unnatural juxtaposition of murine CDR regions with human variable framework region can result in unnatural conformational restraints, which, unless corrected by substitution of certain amino acid residues, lead to loss of binding affinity.
- the selection of amino acid residues for substitution is determined, in part, by computer modeling.
- Computer hardware and software are described herein for producing three-dimensional images of immunoglobulin molecules.
- molecular models are produced starting from solved structures for immunoglobulin chains or domains thereof.
- the chains to be modeled are compared for amino acid sequence similarity with chains or domains of solved three-dimensional structures, and the chains or domains showing the greatest sequence similarity is/are selected as starting points for construction of the molecular model.
- Chains or domains sharing at least 50% sequence identity are selected for modeling, and preferably those sharing at least 60%, 70%, 80%, 90% sequence identity or more are selected for modeling.
- the solved starting structures are modified to allow for differences between the actual amino acids in the immunoglobulin chains or domains being modeled, and those in the starting structure.
- the modified structures are then assembled into a composite immunoglobulin.
- the model is refined by energy minimization and by verifying that all atoms are within appropriate distances from one another and that bond lengths and angles are within chemically acceptable limits.
- amino acid residues for substitution can also be determined, in part, by examination of the characteristics of the amino acids at particular locations, or empirical observation of the effects of substitution or mutagenesis of particular amino acids. For example, when an amino acid differs between a murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid should usually be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid:
- a CDR region e.g., is within about 3-6 ⁇ of a CDR region as determined by computer modeling
- Residues which “noncovalently bind antigen directly” include amino acids in positions in framework regions which have a good probability of directly interacting with amino acids on the antigen according to established chemical forces, for example, by hydrogen bonding, Van der Waals forces, hydrophobic interactions, and the like.
- CDR and framework regions are as defined by Kabat et al. or Chothia et al., supra.
- framework residues as defined by Kabat et al., supra, constitute structural loop residues as defined by Chothia et al., supra
- the amino acids present in the mouse antibody may be selected for substitution into the humanized antibody.
- Residues which are “adjacent to a CDR region” include amino acid residues in positions immediately adjacent to one or more of the CDRs in the primary sequence of the humanized immunoglobulin chain, for example, in positions immediately adjacent to a CDR as defined by Kabat, or a CDR as defined by Chothia (See e.g., Chothia and Lesk JMB 196:901 (1987)).
- amino acids are particularly likely to interact with the amino acids in the CDRs and, if chosen from the acceptor, to distort the donor CDRs and reduce affinity.
- the adjacent amino acids may interact directly with the antigen (Amit et al., Science, 233:747 (1986), which is incorporated herein by reference) and selecting these amino acids from the donor may be desirable to keep all the antigen contacts that provide affinity in the original antibody.
- Residues that “otherwise interact with a CDR region” include those that are determined by secondary structural analysis to be in a spatial orientation sufficient to affect a CDR region.
- residues that “otherwise interact with a CDR region” are identified by analyzing a three-dimensional model of the donor immunoglobulin (e.g., a computer-generated model).
- a three-dimensional model typically of the original donor antibody, shows that certain amino acids outside of the CDRs are close to the CDRs and have a good probability of interacting with amino acids in the CDRs by hydrogen bonding, Van der Waals forces, hydrophobic interactions, etc.
- the donor immunoglobulin amino acid rather than the acceptor immunoglobulin amino acid may be selected.
- Amino acids according to this criterion will generally have a side chain atom within about 3 angstrom units (A) of some atom in the CDRs and must contain an atom that could interact with the CDR atoms according to established chemical forces, such as those listed above.
- the 3 ⁇ is measured between their nuclei, but for atoms that do not form a bond, the 3 ⁇ is measured between their Van der Waals surfaces.
- the nuclei must be within about 6 ⁇ (3 ⁇ plus the sum of the Van der Waals radii) for the atoms to be considered capable of interacting. In many cases the nuclei will be from 4 or 5 to 6 ⁇ apart.
- Amino acids that are capable of interacting with amino acids in the CDRs may be identified in yet another way.
- the solvent accessible surface area of each framework amino acid is calculated in two ways: (1) in the intact antibody, and (2) in a hypothetical molecule consisting of the antibody with its CDRs removed. A significant difference between these numbers of about 10 square angstroms or more shows that access of the framework amino acid to solvent is at least partly blocked by the CDRs, and therefore that the amino acid is making contact with the CDRs.
- Solvent accessible surface area of an amino acid may be calculated based on a three-dimensional model of an antibody, using algorithms known in the art (e.g., Connolly, J. Appl. Cryst. 16:548 (1983) and Lee and Richards, J. Mol. Biol. 55:379 (1971), both of which are incorporated herein by reference).
- Framework amino acids may also occasionally interact with the CDRs indirectly, by affecting the conformation of another framework amino acid that in turn contacts the CDRs.
- the amino acids at several positions in the framework are known to be important for determining CDR confirmation (e.g., capable of interacting with the CDRs) in many antibodies (Chothia and Lesk, supra, Chothia et al., supra and Tramontano et al., J. Mol. Biol. 215:175 (1990), all of which are incorporated herein by reference). These authors identified conserved framework residues important for CDR conformation by analysis of the structures of several known antibodies. The antibodies analyzed fell into a limited number of structural or “canonical” classes based on the conformation of the CDRs. conserveed framework residues within members of a canonical class are referred to as “canonical” residues.
- Canonical residues include residues 2, 25, 29, 30, 33, 48, 64, 71, 90, 94 and 95 of the light chain and residues 24, 26, 29, 34, 54, 55, 71 and 94 of the heavy chain.
- Additional residues e.g., CDR structure-determining residues
- CDR structure-determining residues can be identified according to the methodology of Martin and Thorton (1996) J. Mol. Biol. 263:800.
- the amino acids at positions 2, 48, 64 and 71 of the light chain and 26-30, 71 and 94 of the heavy chain are known to be capable of interacting with the CDRs in many antibodies.
- the amino acids at positions 35 in the light chain and 93 and 103 in the heavy chain are also likely to interact with the CDRs.
- residues which may effect conformation of the CDRs can be identified according to the methodology of Foote and Winter (1992) J. Mol. Biol. 224:487. Such residues are termed “vernier” residues and are those residues in the framework region closely underlying (i.e., forming a “platform” under) the CDRs. At all these numbered positions, choice of the donor amino acid rather than the acceptor amino acid (when they differ) to be in the humanized immunoglobulin is preferred. On the other hand, certain residues capable of interacting with the CDR region, such as the first 5 amino acids of the light chain, may sometimes be chosen from the acceptor immunoglobulin without loss of affinity in the humanized immunoglobulin.
- Residues which “participate in the VL-VH interface” or “packing residues” include those residues at the interface between VL and VH as defined, for example, by Novotny and Haber, Proc. Natl. Acad. Sci. USA, 82:4592-66 (1985) or Chothia et al, supra.
- rare packing residues should be retained in the humanized antibody if they differ from those in the human frameworks.
- one or more of the amino acids fulfilling the above criteria can be substituted. In some embodiments, all or most of the amino acids fulfilling the above criteria are substituted. Occasionally, there is some ambiguity about whether a particular amino acid meets the above criteria, and alternative variant immunoglobulins are produced, one of which has that particular substitution, the other of which does not. Alternative variant immunoglobulins so produced can be tested in any of the assays described herein for the desired activity, and the preferred immunoglobulin selected.
- the CDR regions in humanized antibodies are substantially identical, and more usually, identical to the corresponding CDR regions of the donor antibody.
- one or more residues of a CDR are altered to modify binding to achieve a more favored on-rate of binding, a more favored off-rate of binding, or both, such that an idealized binding constant is achieved.
- an antibody having ultra high binding affinity of, for example, 10 10 M ⁇ 1 or more can be achieved.
- the donor CDR sequence is referred to as a base sequence from which one or more residues are then altered.
- Affinity maturation techniques can be used to alter the CDR region(s) followed by screening of the resultant binding molecules for the desired change in binding.
- the method may also be used to alter the donor CDR, typically a mouse CDR, to be less immunogenic such that a potential human anti-mouse antibody (HAMA) response is minimized or avoided.
- HAMA human anti-mouse antibody
- the CDR regions of the antibody are analyzed to determine the contributions of each individual CDR to antibody binding and/or immunogenicity by systemically replacing each of the donor CDRs with a human counterpart.
- the resultant panel of humanized antibodies is then scored for antigen affinity and potential immunogenicity of each CDR. In this way, the two clinically important properties of a candidate binding molecule, i.e., antigen binding and low immunogenicity, are determined.
- the CDR can then be reengineered to retain only the SDRs and be human and/or minimally immunogenic at the remaining amino acid positions throughout the CDR.
- Such an approach, where only a portion of the donor CDR is grafted, is also referred to as abbreviated CDR-graffing (for technical details on the foregoing techniques, see, e.g., Tamura et al., J. of Immunology 164(3):143241. (2000); Gonzales et al., Mol. Immunol 40:337-349 (2003); Kashmiri et al., Crit. Rev. Oncol. Hematol. 38:3-16 (2001); and De Pascalis et al., J. of Immunology 169(6):3076-84. (2002).
- conservative amino acid substitutions are intended combinations such as gly, ala; val, ile, leu; asp, glu; asn, gln; ser, thr; lys, arg; and phe, tyr.
- acceptor human framework amino acids that are “rare” for a human immunoglobulin at that position. These amino acids can be substituted with amino acids from the equivalent position of the mouse donor antibody or from the equivalent positions of more typical human immunoglobulins. For example, substitution may be desirable when the amino acid in a human framework region of the acceptor immunoglobulin is rare for that position and the corresponding amino acid in the donor immunoglobulin is common for that position in human immunoglobulin sequences; or when the amino acid in the acceptor immunoglobulin is rare for that position and the corresponding amino acid in the donor immunoglobulin is also rare, relative to other human sequences.
- a residue is rare for acceptor human framework sequences should also be considered when selecting residues for backmutation based on contribution to CDR conformation. For example, if backmutation results in substitution of a residue that is rare for acceptor human framework sequences, a humanized antibody may be tested with and without for activity. If the backmutation is not necessary for activity, it may be eliminated to reduce immunogenicity concerns.
- These criteria help ensure that an atypical amino acid in the human framework does not disrupt the antibody structure.
- the humanized antibody may be made less immunogenic.
- rare indicates an amino acid occurring at that position in less than about 20%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 3%, even more preferably less than about 2% and even more preferably less than about 1% of sequences in a representative sample of sequences
- common indicates an amino acid occurring in more than about 25% but usually more than about 50% of sequences in a representative sample. For example, when deciding whether an amino acid in a human acceptor sequence is “rare” or “common”, it will often be preferable to consider only human variable region sequences and when deciding whether a mouse amino acid is “rare” or “common”, only mouse variable region sequences.
- Additional candidates for substitution are acceptor human framework amino acids that would be identified as part of a CDR region under the alternative definition proposed by Chothia et al., supra. Additional candidates for substitution are acceptor human framework amino acids that would be identified as part of a CDR region under the AbM and/or contact definitions.
- Rare donor framework residues are those that are rare (as defined herein) for murine antibodies at that position.
- the subgroup can be determined according to Kabat and residue positions identified which differ from the consensus. These donor specific differences may point to somatic mutations in the murine sequence which enhance activity.
- Rare residues that are predicted to affect binding e.g., packing canonical and/or vernier residues
- Rare residues within the 12A11 v1 sequence include 185 (3.6%).
- Rare residues within the 12A11 vh sequence include T3 (1.0%), I11 (1.7%), L12 (1.7%), S41 (2.8%), D83 (1.8%) and A85 (1.8%).
- Additional candidates for substitution are non-germline residues occurring in an acceptor framework region.
- an acceptor antibody chain i.e., a human antibody chain sharing significant sequence identity with the donor antibody chain
- a germline antibody chain likewise sharing significant sequence identity with the donor chain
- residues not matching between acceptor chain framework and the germline chain framework can be substituted with corresponding residues from the germline sequence.
- the framework regions of humanized immunoglobulins are usually substantially identical, and more usually, identical to the framework regions of the human antibodies from which they were derived.
- many of the amino acids in the framework region make little or no direct contribution to the specificity or affinity of an antibody.
- many individual conservative substitutions of framework residues can be tolerated without appreciable change of the specificity or affinity of the resulting humanized immunoglobulin.
- the variable framework region of the humanized immunoglobulin shares at least 85% sequence identity to a human variable framework region sequence or consensus of such sequences.
- variable framework region of the humanized immunoglobulin shares at least 90%, preferably 95%, more preferably 96%, 97%, 98% or 99% sequence identity to a human variable framework region sequence or consensus of such sequences. In general, however, such substitutions are undesirable.
- the humanized antibodies of the invention exhibit a specific binding affinity for antigen of at least 10 7 , 10 8 , 10 9 or 10 10 M ⁇ 1 .
- the antibodies of the invention can have binding affinities of at least 10 10 , 10 11 or 10 12 M ⁇ 1 .
- the upper limit of binding affinity of the humanized antibodies for antigen is within a factor of three, four or five of that of the donor immunoglobulin.
- the lower limit of binding affinity is also within a factor of three, four or five of that of donor immunoglobulin.
- the binding affinity can be compared to that of a humanized antibody having no substitutions (e.g., an antibody having donor CDRs and acceptor FRs, but no FR substitutions).
- the binding of the optimized antibody (with substitutions) is preferably at least two- to three-fold greater, or three- to four-fold greater, than that of the unsubstituted antibody.
- activity of the various antibodies can be determined, for example, by BIACORE (i.e., surface plasmon resonance using unlabelled reagents) or competitive binding assays.
- humanized antibodies of the invention include a variable region framework sequence selected from human antibody genes (e.g., germline antibody gene segments) which include one or more canonical CDR structure types that are identical or similar to the canonical CDR structure types for the corresponding non-human antibody (e.g., murine) which is humanized.
- human antibody genes e.g., germline antibody gene segments
- canonical CDR structure types that are identical or similar to the canonical CDR structure types for the corresponding non-human antibody (e.g., murine) which is humanized.
- humanized antibodies comprising a framework region having a consensus amino acid sequence, for example, as described in U.S. Pat. No. 6,300,064, incorporated by reference herein in its entirety for all purposes.
- the following table lists various consensus sequences that can be used as framework regions in the humanized antibodies described herein. Therefore, any one of the consensus sequences shown below can be used as in combination with one or more CDRs described herein, thereby resulting in a humanized immunoglobulin or humanized antibody of the invention.
- Yet another strategy that can be used to produce the humanized antibodies of the invention is to select the closest human germline sequence as the framework which receives the CDRs from a murine antibody to be humanized. See, Mercken et al., US 2005/0129695 (incorporated by reference in their entirety for all purposes). Germline sequences originate from un-rearranged immunoglobulin genes and therefore do not present somatic hypermtuation that is potentially immunogenic. This approach is based on the search for the closest human germline sequence.
- variable domains from germline sequences that exhibit a high degree of sequence identity with the murine VL and VH framework regions can be identified using the V-Base and/or IMGT databases (publicly accessible through the Medical Research Council Center for Protein Engineering internet server and the European Bioinformatics Institute internet server, respectively).
- the murine CDRs are then grafted on to the chosen human germline variable region acceptor sequences.
- framework residues can be analyzed using any of the techniques as described above to determine which, if any, residues should be substituted to optimize the properties of the resulting humanized antibody. For example, computer modeling can be used to identify residues which have a good probability of directly or indirectly influencing antigen binding.
- a preferred embodiment of the present invention features a humanized antibody to the N-terminus of A ⁇ , in particular, for use in the therapeutic and/or diagnostic methodologies described herein.
- a particularly preferred starting material for production of humanized antibodies is the monoclonal antibody 12A11.
- 12A11 is specific for the N-terminus of A ⁇ and has been shown to (1) have a high avidity for aggregated A ⁇ 1-42, (2) have the ability to capture soluble A ⁇ , and (3) mediate phagocytosis (e.g., induce phagocytosis) of amyloid plaque (see Example I).
- the in vivo efficacy of the 12A11 antibody is described in Example H.
- the cloning and sequencing of cDNA encoding the 12A11 antibody heavy and light chain variable regions is described in Example III.
- Suitable human acceptor antibody sequences can be identified by computer comparisons of the amino acid sequences of the mouse variable regions with the sequences of known human antibodies. The comparison is performed separately for heavy and light chains but the principles are similar for each.
- variable domains from human antibodies whose framework sequences exhibit a high degree of sequence identity with the murine VL and VH framework regions are identified by query of, for example, the Kabat Database or the IgG Protein Sequence Database using NCBI IgG BLAST (publicly accessible through the National Institutes of Health NCBI internet server) with the respective murine framework sequences.
- acceptor sequences sharing greater that 50% sequence identity with murine donor sequences, e.g., donor framework (FR) sequences are selected.
- acceptor antibody sequences sharing 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% sequence identity or more are selected.
- 12A11 light chain shows the greatest sequence identity to human light chains of subtype kappa II
- 12A11 heavy chain shows greatest sequence identity to human heavy chains of subtype II, as defined by Kabat et al., supra.
- Light and heavy human framework regions can be derived from human antibodies of these subtypes, or from consensus sequences of such subtypes.
- light chain variable framework regions were derived from human subgroup II antibodies. Based on previous experiments designed to achieve high levels of expression of humanized antibodies having heavy chain variable framework regions derived from human subgroup II antibodies, it had been discovered that expression levels of such antibodies were sometimes low. Accordingly, based on the reasoning described in Saldanha et al. (1999) Mol Immunol. 36:709-19, framework regions from human subgroup III antibodies were chosen rather than human subgroup II.
- a human subgroup II antibody K64(AIMS4) (accession no. BAC01733 (SEQ ID NO: 8)) was identified from the NCBI non-redundant database having significant sequence identity within the light chain variable regions of 12A11.
- a human subgroup III antibody M72 (accession no. AAA69734 (SEQ ID NO: 11) was identified from the NCBI non-redundant database having significant sequence identity within the heavy chain variable regions of 12A 11 (see also Schroeder and Wang (1990) Proc. Natl. Acad. Sci. U.S.A. 872: 6146-6150.
- Alternative light chain acceptor sequences include, for example, PDB Accession No. 1KFA (gi24158782), PDB Accession No. 1KFA (gi24158784), EMBL Accession No. CAE75574.1 (gi38522587), EMBL Accession No. CAE75575.1 (gi38522590), EMBL Accession No. CAE84952.1 (gi39838891), DJB Accession No. BAC01734.1 (gi21669419), DJB Accession No. BAC01730.1 (gi21669411), PIR Accession No. S40312 (gi481978), EMBL Accession No. CAA51090.1 (gi3980118), GenBank Accession No.
- AAH63599.1 (gi39794308), PIR Accession No. S22902 (gi106540), PIR Accession No. S42611 (gi631215), EMBL Accession No. CAA38072.1 (gi433890), GenBank Accession No. AAD00856.1 (gi4100384), EMBL Accession No. CAA39072.1 (gi34000), PIR Accession No. S23230 (gi284256), DBJ Accession No. BAC01599.1 (gi21669149), DBJ Accession No. BAC01729.1 (gi21669409), DBJ Accession No. BAC01562.1 (gi21669075), EMBL Accession No.
- CAA85590.1 (gi587338), GenBank Accession No. AAQ99243.1 (gi37694665), GenBank Accession No. AAK94811.1 (gi18025604), EMBL Accession No. CAB51297.1 (gi5578794), DBJ Accession No. BACO 1740.1 (gi21669431), and DBJ Accession No. BACO 1733.1 (gi21669417).
- Alternative heavy chain acceptor sequences include, for example, GenBank Accession No. AAB35009.1 (gi1041885), DBJ Accession No. BAC01904.1 (gi21669789), GenBank Accession No. AAD53816.1 (gi5834100), GenBank Accession No.
- AAS86081.1 (gi46254223), DBJ Accession No. BAC01462.1 (gi21668870), GenBank Accession No. AAC18191.1 (gi3170773), DBJ Accession No. BAC02266.1 (gi21670513), GenBank Accession No. AAD56254.1 (gi5921589), GenBank Accession No. AAD53807.1 (gi5834082), DBJ Accession No. BAC02260.1 (gi21670501), GenBank Accession No. AAC18166.1 (gi3170723), EMBL Accession No. CAA49495.1 (gi33085), PIR Accession No. S31513 (gi345903), GenBank Accession No.
- AAS86079.1 (gi46254219), DBJ Accession No. BAC01917.1 (gi21669815), DBJ Accession No. BAC01912.1 (gi21669805), GenBank Accession No. AAC 18283.1 (gi3170961), DBJ Accession No. BAC01903 (gi21669787), DBJ Accession NO. BAC01887.1 (gi21669755), DBJ Accession No. BAC02259.1 (gi21370499), DBJ Accession No. BAC01913.1 (gi21669807), DBJ Accession No. BAC01910.1 (gi21669801), DJB Accession No.
- BAC02267.1 (gi21670515), GenBank Accession No. AAC18306.1 (gi3171011), GenBank Accession No. AAD53817.1 (gi5834102), PIR Accession No. E36005 (gi106423), EMBL CAB37129.1 (gi4456494) and GenBank AAA68892.1 (gi186190).
- humanized antibodies of the invention include 12A11 CDRs and FRs from an acceptor sequence listed supra. Residues within the framework regions important for CDR conformation and/or activity as described herein are selected for backmutation (if differing between donor and acceptor sequences).
- Residues are next selected for substitution, as follows.
- the human framework amino acid should usually be substituted by the equivalent mouse amino acid if it is reasonably expected that the amino acid:
- Example VI Structural analysis of the 12A11 antibody heavy and light chain variable regions, and humanization of the 12A11 antibody is described in Example VI. Briefly, three-dimensional models for the solved murine antibody structures 1 KTR for the light chain and 1 JRH and 1 ETZ for the heavy chain were studied. Alternative three-dimensional models which can be studied for identification of residues, important for CDR confirmation (e.g., vernier residues), include PDB Accession No. 2JEL (gi3212688), PDB Accession No. 1TET (gi494639), PDB Accession No. IJP5 (gi16975307), PDB Accession No. 1CBV (gi493917), PDB Accession No. 2PCP (gi4388943), PDB Accession No.
- Three-dimensional structural information for the antibodies described herein is publicly available, for example, from the Research Collaboratory for Structural Bioinformatics' Protein Data Bank (PDB).
- PDB is freely accessible via the World Wide Web internet and is described by Berman et al. (2000) Nucleic Acids Research, 28:235.
- Study of solved three-dimensional structures allows for the identification of CDR-interacting residues within 12A11.
- three-dimensional models for the 12A11 VH and VL chains can be generated using computer modeling software. Briefly, a three-dimensional model is generated based on the closest solved murine antibody structures for the heavy and light chains.
- 1KTR can be used as a template for modeling the 12A11 light chain
- 1ETZ and 1JRH used as templates for modeling the heavy chain.
- the model can be further refined by a series of energy minimization steps to relieve unfavorable atomic contacts and optimize electrostatic and van der Waals interactions. Additional three-dimensional analysis and/or modeling can be performed using 2JEL (2.5 ⁇ ) and/or 1TET (2.3 ⁇ ) for the light chain and 1GGI (2.8 ⁇ ) for the heavy chain (or other antibodies set forth supra) based on the similarity between these solved murine structures and the respective 12A11 chains.
- the computer model of the structure of 12A11 can further serve as a starting point for predicting the three-dimensional structure of an antibody containing the 12A11 complementarity determining regions substituted in human framework structures. Additional models can be constructed representing the structure as further amino acid substitutions are introduced.
- the humanized antibodies of the present invention will usually contain a substitution of a human light chain framework residue with a corresponding 12A11 residue in at least 1, 2, 3 or more of the chosen positions.
- the humanized antibodies also usually contain a substitution of a human heavy chain framework residue with a corresponding 12A11 residue in at least 1, 2, 3 or more of the chosen positions.
- Rare mouse residues are identified by comparing the donor VL and/or VH sequences with the sequences of other members of the subgroup to which the donor VL and/or VH sequences belong (according to Kabat) and identifying the residue positions which differ from the consensus. These donor specific differences may point to somatic mutations which enhance activity. Rare residues close to the binding site may possibly contact the antigen, making it desirable to retain the mouse residue. However, if the rare mouse residue is not important for binding, use of the corresponding acceptor residue is preferred as the mouse residue may create immunogenic neoepitopes in the humanized antibody. In the situation where a rare residue in the donor sequence is actually a common residue in the corresponding acceptor sequence, the preferred residue is clearly the acceptor residue.
- Table 1 summarizes the sequence analysis of the 12A11 VH and VL regions.
- Germline sequences are set forth that can be used in selecting amino acid substitutions.
- IgG BLASTTM Homology searching of the NCBI “Ig Germline Genes” database is provided by IgG BLASTTM.
- a humanized antibody of the present invention contains (i) a light chain comprising a variable domain comprising murine 12A11 VL CDRs and a human acceptor framework, the framework having zero, one, two, three, four, five, six, seven, eight, nine or more residues substituted with the corresponding 12A11 residue and (ii) a heavy chain comprising 12A11 VH CDRs and a human acceptor framework, the framework having at least one, two, three, four, five, six, seven, eight, nine or more residues substituted with the corresponding 12A11 residue, and, optionally, at least one, preferably two or three residues substituted with a corresponding human germline residue.
- a humanized antibody of the present invention contains (i) a light chain comprising a variable domain comprising murine 12A11 VL CDRs and a human acceptor framework, the framework having at least one, two, three, four, five, six, seven, eight, nine or more residues backmutated (i.e., substituted with the corresponding 12A11 residue), wherein the backmutation(s) are at a canonical, packing and/or vernier residues and (ii) a heavy chain comprising 12A11 VH CDRs and a human acceptor framework, the framework having at least one, two, three, four, five, six, seven, eight, nine or more residues backmutated, wherein the backmutation(s) are at a canonical, packing and/or vernier residues.
- backmutations are only at packing and/or canonical residues or are primarily at canonical and/or packing residues (e.g., only 1 or 2 vernier residues of the vernier residues differing between the donor and acceptor sequence are backmutated).
- humanized antibodies include the fewest number of backmutations possible while retaining a binding affinity comparable to that of the donor antibody (or a chimeric version thereof).
- various combinations of backmutations can be eliminated and the resulting antibodies tested for efficacy (e.g., binding affinity).
- backmutations e.g., 1, 2, 3, or 4 backmutations
- backmutations at vernier residues can be eliminated or backmutations at combinations of vernier and packing, vernier and canonical or packing and canonical residues can be eliminated.
- a humanized antibody of the present invention has structural features, as described herein, and further has at least one (preferably two, three, four or all) of the following activities: (I) binds soluble A ⁇ ; (2) binds aggregated A ⁇ 1-42 (e.g., as determined by ELISA); (3) captures soluble A ⁇ ; (4) binds A ⁇ in plaques (e.g., staining of AD and/or PDAPP plaques); (5) binds A ⁇ with an affinity no less than two to three fold lower than chimeric 12A11 (e.g., 12A11 having murine variable region sequences and human constant region sequences); (6) mediates phagocytosis of A ⁇ (e.g., in an ex vivo phagocytosis assay, as described herein); and (7) crosses the blood-brain barrier (e.g., demonstrates short-term brain localization, for example, in a PDAPP animal model, as described herein).
- a humanized antibody of the present invention has structural features, as described herein, such that it binds A ⁇ in a manner or with an affinity sufficient to elicit at least one of the following in vivo effects: (1) reduce A ⁇ plaque burden; (2) prevent plaque formation; (3) reduce levels of soluble A ⁇ ; (4) reduce the neuritic pathology associated with an amyloidogenic disorder; (5) lessen or ameliorate at least one physiological symptom associated with an amyloidogenic disorder; and/or (6) improve cognitive function.
- a humanized antibody of the present invention has structural features, as described herein, and specifically binds to an epitope comprising residues 3-7 of A ⁇ .
- a humanized antibody of the present invention has structural features, as described herein, such that it binds to an N-terminal epitope within A ⁇ (e.g., binds to an epitope within amino acids 3-7 of A ⁇ ), and is capable of reducing (1) A ⁇ peptide levels; (2) A ⁇ plaque burden; and (3) the neuritic burden or neuritic dystrophy associated with an amyloidogenic disorder.
- Activities described above can be determined utilizing any one of a variety of assays described herein or in the art (e.g., binding assays, phagocytosis assays, etc.). Activities can be assayed either in vivo (e.g., using labeled assay components and/or imaging techniques) or in vitro (e.g., using samples or specimens derived from a subject). Activities can be assayed either directly or indirectly. In certain preferred embodiments, neurological endpoints (e.g., amyloid burden, neuritic burden, etc) are assayed.
- assays described herein or in the art e.g., binding assays, phagocytosis assays, etc.
- Activities can be assayed either in vivo (e.g., using labeled assay components and/or imaging techniques) or in vitro (e.g., using samples or specimens derived from a subject). Activities can be assayed either directly or indirectly.
- Such endpoints can be assayed in living subjects (e.g., in animal models of Alzheimer's disease or in human subjects, for example, undergoing immunotherapy) using non-invasive detection methodologies. Alternatively, such endpoints can be assayed in subjects post mortem. Assaying such endpoints in animal models and/or in human subjects post mortem is useful in assessing the effectiveness of various agents (e.g., humanized antibodies) to be utilized in similar immunotherapeutic applications. In other preferred embodiments, behavioral or neurological parameters can be assessed as indicators of the above neuropathological activities or endpoints.
- agents e.g., humanized antibodies
- one or more of the murine complementarity determining regions (CDR) of the heavy and/or light chain of the antibody can be humanized, for example, placed in the context of one or more human framework regions, using primer-based polymerase chain reaction (PCR). Briefly, primers are designed which are capable of annealing to target murine CDR region(s) which also contain sequence which overlaps and can anneal with a human framework region.
- the primers can amplify a murine CDR from a murine antibody template nucleic acid and add to the amplified template a portion of a human framework sequence.
- primers can be designed which are capable of annealing to a target human framework region(s) where a PCR reaction using these primers results in an amplified human framework region(s).
- the murine CDR region having overlapping human framework sequence with the amplified human framework sequence, can be genetically linked. Accordingly, in one or more such reactions, one or more murine CDR regions can be genetically linked to intervening human framework regions.
- the primers may also comprise desirable restriction enzyme recognition sequences to facilitate the genetic engineering of the resultant PCR amplified sequences into a larger genetic segment, for example, a variable light or heavy chain segment, heavy chain, or vector.
- the primers used to amplify either the murine CDR regions or human framework regions may have desirable mismatches such that a different codon is introduced into the murine CDR or human framework region. Typical mismatches introduce alterations in the human framework regions that preserve or improve the structural orientation of the murine CDR and thus its binding affinity, as described herein.
- nucleic acid sequences will encode each immunoglobulin amino acid sequence.
- the desired nucleic acid sequences can be produced by de novo solid-phase DNA synthesis or by PCR mutagenesis of an earlier prepared variant of the desired polynucleotide.
- Oligonucleotide-mediated mutagenesis is a preferred method for preparing substitution, deletion and insertion variants of target polypeptide DNA. See Adelman et al., DNA 2:183 (1983). Briefly, the target polypeptide DNA is altered by hybridizing an oligonucleotide encoding the desired mutation to a single-stranded DNA template. After hybridization, a DNA polymerase is used to synthesize an entire second complementary strand of the template that incorporates the oligonucleotide primer, and encodes the selected alteration in the target polypeptide DNA.
- variable segments of antibodies produced as described supra are typically linked to at least a portion of an immunoglobulin constant region (Fc region), typically that of a human immunoglobulin.
- Fc region immunoglobulin constant region
- Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells, but preferably immortalized B cells (see Kabat et al., supra, and Liu et al., WO87/02671) (each of which is incorporated by reference in its entirety for all purposes).
- the antibody will contain both light chain and heavy chain constant regions.
- the heavy chain constant region usually includes CH1, hinge, CH2, CH3, and CH4 regions.
- the antibodies described herein include antibodies having all types of constant regions, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and IgG4.
- the constant domain is usually a complement fixing constant domain and the class is typically IgG 1.
- Human isotypes IgG1 and IgG4 are exemplary.
- Light chain constant regions can be lambda or kappa.
- the humanized antibody may comprise sequences from more than one class or isotype.
- Antibodies can be expressed as tetramers containing two light and two heavy chains, as separate heavy chains, light chains, as Fab, Fab′F(ab′)2, and Fv, or as single chain antibodies in which heavy and light chain variable domains are linked through a spacer.
- a humanized antibody of the invention includes the 12A11v.1 VH region linked to an IgG1 constant region, as shown below in SEQ ID NO: 52.
- a humanized antibody of the invention includes the 12A11 v.1 VH region linked to an IgG4 constant region, as shown below in SEQ ID NO:53.
- a humanized antibody of the invention includes a 12A11 v3.1 VH region linked to an IgG1 or an IgG4 constant region, as shown below in SEQ ID NOs:54 and 55, respectively.
- the terminal lysine as shown in parenthesis, is optionally expressed.
- humanized antibodies described herein are modified to enhance their antigen dependent cellular cytotoxicity (ADCC) activity using techniques, such as, for example, those described in U.S. Pat. No. 6,946,292, the entire contents of which are incorporated by reference herein.
- ADCC activity of antibodies is generally thought to require the binding of the Fc region of an antibody to an antibody receptor existing on the surface of an effector cell, such as, for example, a killer cell, a natural killer cell and an activated macrophage.
- the ADCC activity of the antibody can be enhanced in vitro by, for example, 10-fold, or 20-fold, or 30-fold, or 40-fold, or 50-fold, or 100-fold, relative to an unmodified humanized antibody. Because of increased ADCC activity, such modified antibodies can be used at lower dosages than their unmodified counterparts and generally have fewer or reduced side effects in patients.
- aglycosyl versions of humanized antibodies are featured, wherein such antibodies include an aglycosylated constant region.
- Oligosaccharide at Asn-297 is a characteristic feature of normal human IgG antibodies (See, Kabat et al., 1987, Sequence of Proteins of Immunological Interest, U.S.
- Each of the two heavy chains in IgG molecules have a single branched chain carbohydrate group which is linked to the amide group of the asparagine residue, for example, at position 297.
- Substitution of, for example, asparagine with alanine prevents the glycosylation of the antibody, as described in, for example, U.S. Pat. No. 6,706,265, incorporated by reference herein.
- the amino acid residue Asn at position 297 is mutated to alanine.
- Chimeric and humanized antibodies are typically produced by recombinant expression.
- Nucleic acids encoding light and heavy chain variable regions, optionally linked to constant regions, are inserted into expression vectors.
- the light and heavy chains can be cloned in the same or different expression vectors.
- the DNA segments encoding immunoglobulin chains are operably linked to control sequences in the expression vector(s) that ensure the expression of immunoglobulin polypeptides.
- Expression control sequences include, but are not limited to, promoters (e.g., naturally-associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences.
- the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells (e.g., COS or CHO cells).
- eukaryotic host cells e.g., COS or CHO cells.
- expression vectors are typically replicable in the host organisms either as episomes or as an integral part of the host chromosomal DNA.
- expression vectors contain selection markers (e.g., ampicillin-resistance, hygromycin-resistance, tetracycline resistance, kanamycin resistance or neomycin resistance) to permit detection of those cells transformed with the desired DNA sequences (see, e.g., Itakura et al., U.S. Pat. No. 4,704,362).
- E. coli is one prokaryotic host particularly useful for cloning the polynucleotides (e.g., DNA sequences) of the present invention.
- Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis , and other enterobacteriaceae, such as Salmonella, Serratia , and various Pseudomonas species.
- bacilli such as Bacillus subtilis
- enterobacteriaceae such as Salmonella, Serratia
- various Pseudomonas species include Salmonella, Serratia , and various Pseudomonas species.
- expression vectors which will typically contain expression control sequences compatible with the host cell (e.g., an origin of replication).
- any number of a variety of well-known promoters will be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda.
- the promoters will typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation.
- yeast Other microbes, such as yeast, are also useful for expression.
- Saccharomyces is a preferred yeast host, with suitable vectors having expression control sequences (e.g., promoters), an origin of replication, termination sequences and the like as desired.
- Typical promoters include 3-phosphoglycerate kinase and other glycolytic enzymes.
- Inducible yeast promoters include, among others, promoters from alcohol dehydrogenase, isocytochrome C, and enzymes responsible for maltose and galactose utilization.
- mammalian tissue cell culture may also be used to express and produce the polypeptides of the present invention (e.g., polynucleotides encoding immunoglobulins or fragments thereof). See Winnacker, From Genes to Clones, VCH Publishers, N.Y., N.Y. (1987).
- Eukaryotic cells are actually preferred, because a number of suitable host cell lines capable of secreting heterologous proteins (e.g., intact immunoglobulins) have been developed in the art, and include CHO cell lines, various Cos cell lines, HeLa cells, preferably, myeloma cell lines, or transformed B-cells or hybridomas.
- the cells are nonhuman.
- Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (Queen et al., Immunol. Rev. 89:49 (1986)), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
- Preferred expression control sequences are promoters derived from immunoglobulin genes, SV40, adenovirus, bovine papilloma virus, cytomegalovirus and the like. See Co et al., J. Immunol. 148:1149 (1992).
- antibody-coding sequences can be incorporated in transgenes for introduction into the genome of a transgenic animal and subsequent expression in the milk of the transgenic animal (see, e.g., Deboer et al., U.S. Pat. No. 5,741,957, Rosen, U.S. Pat. No. 5,304,489, and Meade et al., U.S. Pat. No. 5,849,992).
- Suitable transgenes include coding sequences for light and/or heavy chains in operable linkage with a promoter and enhancer from a mammary gland specific gene, such as casein or beta lactoglobulin.
- antibodies e.g., humanized antibodies
- transgenic plants e.g., tobacco, maize, soybean and alfalfa.
- Improved ‘plantibody’ vectors Hendy et al. (1999) J. Immunol. Methods 231:137-146) and purification strategies coupled with an increase in transformable crop species render such methods a practical and efficient means of producing recombinant immunoglobulins not only for human and animal therapy, but for industrial applications as well (e.g., catalytic antibodies).
- plant produced antibodies have been shown to be safe and effective and avoid the use of animal-derived materials and therefore the risk of contamination with a transmissible spongiform encephalopathy (TSE) agent.
- TSE transmissible spongiform encephalopathy
- antibody heavy and light chains can be independently cloned into expression vectors (e.g., Agrobacterium tumefaciens vectors), followed by the transformation of plant tissue in vitro with the recombinant bacterium or direct transformation using, e.g., particles coated with the vector which are then physically introduced into the plant tissue using, e.g., ballistics. Subsequently, whole plants expressing individual chains are reconstituted followed by their sexual cross, ultimately resulting in the production of a fully assembled and functional antibody. Similar protocols have been used to express functional antibodies in tobacco plants (see Hiatt et al. (1989) Nature 342:76-87).
- expression vectors e.g., Agrobacterium tumefaciens vectors
- signal sequences may be utilized to promote the expression, binding and folding of unassembled antibody chains by directing the chains to the appropriate plant environment (e.g., the aqueous environment of the apoplasm or other specific plant tissues including tubers, fruit or seed) (see Fiedler et al. (1995) Bio/Technology 13:1090-1093). Plant bioreactors can also be used to increase antibody yield and to significantly reduce costs.
- the vectors containing the polynucleotide sequences of interest can be transferred into the host cell by well-known methods, which vary depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment, electroporation, lipofection, biolistics or viral-based transfection may be used for other cellular hosts. (See generally Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Press, 2nd ed., 1989) (incorporated by reference in its entirety for all purposes).
- transgenic animals can be microinjected into fertilized oocytes, or can be incorporated into the genome of embryonic stem cells, and the nuclei of such cells transferred into enucleated oocytes.
- the vectors When heavy and light chains are cloned on separate expression vectors, the vectors are co-transfected to obtain expression and assembly of intact immunoglobulins. Once expressed, the whole antibodies, their dimers, individual light and heavy chains, or other immunoglobulin forms of the present invention can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, HPLC purification, gel electrophoresis and the like (see generally Scopes, Protein Purification (Springer-Verlag, N.Y., (1982)). Substantially pure immunoglobulins of at least about 90 to 95% homogeneity are preferred, and 98 to 99% or more homogeneity are most preferred, for pharmaceutical uses.
- antibody fragments are also contemplated within the scope of the instant invention.
- fragments of non-human, and/or chimeric antibodies are provided.
- fragments of humanized antibodies are provided. Typically, these fragments exhibit specific binding to antigen with an affinity of at least 10 7 , and more typically 10 8 or 10 9 M ⁇ 1 .
- Humanized antibody fragments include separate heavy chains, light chains, Fab, Fab′, F(ab′)2, Fabc, and Fv. Fragments are produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
- the generally short half-life of antibody fragments is extended by pegylation.
- This is generally achieved by fusion to polyethylene glycol (PEG), as described by, for example, Leong, et al. Cytokine 16, 106-119 (2001).
- Pegylation has the added advantage of eliminating Fc receptor mediated function, where desired, and/or reducing immunogenicity.
- 2-20 kDa PEG molecules are covalently attached, for example, to an antibody heavy chain hinge region via a K-linker-C (See, e.g., Choy et al., Rheumatol. 41:1133-1137 (2002)).
- Epitope mapping can be performed to determine which antigenic determinant or epitope of A ⁇ is recognized by the antibody.
- epitope mapping is performed according to Replacement NET (rNET) analysis.
- the rNET epitope map assay provides information about the contribution of individual residues within the epitope to the overall binding activity of the antibody.
- rNET analysis uses synthesized systematic single substituted peptide analogs. Binding of an antibody being tested is determined against native peptide (native antigen) and against 19 alternative “single substituted” peptides, each peptide being substituted at a first position with one of 19 non-native amino acids for that position. A profile is generated reflecting the effect of substitution at that position with the various non-native residues.
- Profiles are likewise generated at successive positions along the antigenic peptide.
- the combined profile, or epitope map, (reflecting substitution at each position with all 19 non-native residues) can then be compared to a map similarly generated for a second antibody.
- Substantially similar or identical maps indicate that antibodies being compared have the same or similar epitope specificity.
- Groups of 7-9 month old PDAPP mice each are injected with 0.5 mg in PBS of polyclonal anti-A ⁇ or specific anti-A ⁇ monoclonal, humanized, or chimeric antibodies. All antibody preparations are purified to have low endotoxin levels. Monoclonals can be prepared against a fragment by injecting the fragment or longer form of A ⁇ into a mouse, preparing hybridomas and screening the hybridomas for an antibody that specifically binds to a desired fragment of A ⁇ without binding to other nonoverlapping fragments of A ⁇ . Humanized and/or chimeric antibodies are prepared as described herein.
- mice are injected intraperitoneally as needed over a 4 month period to maintain a circulating antibody concentration measured by ELISA titer of greater than 1/1000 defined by ELISA to A42 or other immunogen. Titers are monitored and mice are euthanized at the end of 6 months of injections. Histochemistry, A ⁇ levels and toxicology are performed post mortem. Ten mice are used per group.
- the invention also provides methods of testing the ability of an antibody to bind to soluble, oligomeric A ⁇ in a biochemical assay.
- the biochemical assay is based, at least in part, on a comparison of the binding of an antibody to one or more forms of soluble, oligomeric A ⁇ (e.g., A ⁇ dimers, A ⁇ trimers, A ⁇ tetramers, A ⁇ pentamers, and the like) as compared to the binding of the antibody to monomeric A ⁇ .
- This comparison can be used to determine a relative binding of the antibody to soluble, oligomeric A ⁇ as compared to monomeric A ⁇ .
- this relative binding is compared to a corresponding relative binding of a control reagent to one or more soluble oligomeric A ⁇ species versus monomeric A ⁇ .
- the affinity of an antibody for one or more oligomeric A ⁇ species is compared to the antibody's affinity for monomeric A ⁇ in the A ⁇ preparation. It has been discovered that a strong correlation exists between an A ⁇ antibody's ability to preferentially bind soluble, oligomeric A ⁇ species and the ability of the antibody to rapidly improve cognition as assessed by a CFC assay in an approporate model animal, as described in detail infra.
- An antibody's ability to improve cognition in the CFC assay is further believed to be a strong indicator or predictor of the antibody's ultimate human therapeutic efficacy (in particular, efficacy in rapidly improving cognition in a patient). Accordingly, a comparison of A ⁇ antibody binding preferences and/or affinities leads to the identification of certain antibodies as candidates for use in the therapeutic methods of the invention, in particular, for use in method for effecting rapid improvement in cognition in a patient.
- Candidate antibodies exhibit a preferential or greater binding to one or more soluble oligomeric A ⁇ species as compared to monomeric A ⁇ .
- Antibodies that preferentially bind to, for example, A ⁇ dimers, trimers and tetramers as compared to monomeric A ⁇ are preferred candidates for use in methods for effecting rapid improvement in cognition in a patient.
- candidate antibodies exhibiting a two-fold, three-fold, four-fold, five-fold, ten-fold, twenty-fold or more greater binding to soluble oligomeric A ⁇ species as compared to monomeric A ⁇ are selected for use in the threapeutic methods.
- the binding of an antibody to one or more soluble, oligomeric A ⁇ species or to monomeric A ⁇ can be determined qualitatively, quantitatively, or combination of both.
- any technique capable of distinguishing oligomeric A ⁇ species from monomeric A ⁇ in an A ⁇ preparation comprising the species can be used.
- one or more of immunoprecipitation, electrophoretic separation, and chromatographic separation e.g., liquid chromatography
- chromatographic separation e.g., liquid chromatography
- the binding of the antibody to one or more soluble, oligomeric A ⁇ species or to monomeric A ⁇ is determined by immunoprecipitating the A ⁇ species from the preparation.
- the immunoprecipitate is then subjected to an electrophoretic separation (e.g., SDS-PAGE) to distinguish oligomeric species from monomeric A ⁇ in the precipitate.
- the amount of oligomeric A ⁇ species and monomeric A ⁇ present in the electrophoretic bands can be visualized, for example, by immunoblotting of the electrophoretic gel or by direct quantitation of the respective species in the bands of the electrophoretic gel.
- the amount of precipitate for an A ⁇ species can be determined, for example, from the intensity of the corresponding electrophoretic bands, immunoblot bands, or a combination of both. The intensity determination can be qualitative, quantitative, or a combination of both.
- Assessment of band intensity can be performed, for example, using appropriate film exposures which can be scanned and the density of bands determined with software, for example, AlphaEaseTM software (AlphalnnotechTM).
- Assessment of band intensity can be performed, for example, using any of a number of labels incorporated into the antibody, an imaging reagent (e.g., an antibody used in an immunoblot), or both.
- Suitable labels include, but are not limited to, fluorescent labels, radioactive labels, paramagnetic labels, or combinations thereof.
- the amount of one or more oligomeric A ⁇ species and/or monomeric A ⁇ which bind to an antibody can be assessed using mass spectrometry, for example, on the A ⁇ preparation itself a suitable time after it has been contacted with the antibody, or on monomeric A ⁇ and/or one or more soluble, oligomeric A ⁇ species bound to the antibody which have been extracted from the A ⁇ preparation.
- the affinity of an antibody for one or more oligomeric A ⁇ species is compared to the antibody's affinity for monomeric A ⁇ to identify the antibody as a candidate for use in the therapeutic methods of the invention, in particular, for use in method for effecting rapid improvement in cognition in a patient.
- the affinity of the test antibody (e.g., an A ⁇ antibody) for oligomeric A ⁇ as compared to monomeric A ⁇ can be compared to the binding affinities of a control reagent.
- Labels can be used to assess the affinity of an antibody for monomeric A ⁇ , oligomeric A ⁇ , or both.
- a primary reagent with affinity for A ⁇ is unlabelled and a secondary labeling agent is used to bind to the primary reagent. Suitable labels include, but are not limited to, fluorescent labels, paramagnetic labels, radioactive labels, and combinations thereof.
- the methods of the invention feature the administration of an anti-A ⁇ antibody that is capable of rapidly improving cognition in a subject wherein the anti-A ⁇ antibody has been identified in using an assay which is suitably predictive of immunotherapeutic efficacy in the subject.
- the assay is a biochemical assay that is based, at least in part, on a comparison of the binding of one or more A ⁇ oligomers in an A ⁇ preparation to a test immunotherapeutic agent to the binding of A ⁇ monomers in the A ⁇ preparation to the test immunotherapeutic agent.
- the one or more AD oligomers can include, for example, one or more of A ⁇ dimers, A ⁇ trimers, A ⁇ tetramers, and A ⁇ pentamers.
- the test immunotherapeutic agent is identified when the binding of one or more A ⁇ oligomers in the A ⁇ preparation to the test immunotherapeutic agent is greater than the binding of A ⁇ monomers in the A ⁇ preparation to the test immunotherapeutic agent.
- the amount of A ⁇ monomers and one or more A ⁇ oligomer species in an A ⁇ preparation which bind to a test immunological reagent can be assessed using biochemical methods, for example using immunoprecipitation to precipitate from the A ⁇ preparation the A ⁇ monomers and one or more A ⁇ oligomer species bound to the test immunological reagent followed by an electrophoretic separation of the immunoprecipitates.
- biochemical assays are discussed further herein and in U.S. Provisional Patent Application Nos. 60/636,687, filed on Dec. 15, 2004, and 60/736,045, filed on Nov. 10, 2005, the entire content of each of which is incorporated by reference herein.
- the invention also provides methods of screening an antibody for activity in clearing an amyloid deposit or any other antigen, or associated biological entity, for which clearing activity is desired.
- a tissue sample from a brain of a patient with Alzheimer's disease or an animal model having characteristic Alzheimer's pathology is contacted with phagocytic cells bearing an Fc receptor, such as microglial cells, and the antibody under test in a medium in vitro.
- the phagocytic cells can be a primary culture or a cell line, and can be of murine (e.g., BV-2 or C8-B4 cells) or human origin (e.g., THP-1 cells).
- the components are combined on a microscope slide to facilitate microscopic monitoring.
- multiple reactions are performed in parallel in the wells of a microtiter dish.
- a separate miniature microscope slide can be mounted in the separate wells, or a nonmicroscopic detection format, such as ELISA detection of A ⁇ can be used.
- a series of measurements is made of the amount of amyloid deposit in the in vitro reaction mixture, starting from a baseline value before the reaction has proceeded, and one or more test values during the reaction.
- the antigen can be detected by staining, for example, with a fluorescently labeled antibody to A ⁇ or other component of amyloid plaques.
- the antibody used for staining may or may not be the same as the antibody being tested for clearing activity.
- a reduction relative to baseline during the reaction of the amyloid deposits indicates that the antibody under test has clearing activity.
- Such antibodies are likely to be useful in preventing or treating Alzheimer's and other amyloidogenic diseases.
- Particularly useful antibodies for preventing or treating Alzheimer's and other amyloidogenic diseases include those capable of clearing both compact and diffuse amyloid plaques, for example, the 12A11 antibody of the instant invention, or chimeric or humanized versions thereof.
- Analogous methods can be used to screen antibodies for activity in clearing other types of biological entities.
- the assay can be used to detect clearing activity against virtually any kind of biological entity.
- the biological entity has some role in human or animal disease.
- the biological entity can be provided as a tissue sample or in isolated form. If provided as a tissue sample, the tissue sample is preferably unfixed to allow ready access to components of the tissue sample and to avoid perturbing the conformation of the components incidental to fixing.
- tissue bearing pathological matrices between cells e.g., fibrinous pericarditis
- tissue bearing aberrant antigens e.g., scar tissue.
- isolated biological entities that can be used include A ⁇ , viral antigens or viruses, proteoglycans, antigens of other pathogenic microorganisms, tumor antigens, and adhesion molecules. Such antigens can be obtained from natural sources, recombinant expression or chemical synthesis, among other means.
- the tissue sample or isolated biological entity is contacted with phagocytic cells bearing Fc receptors, such as monocytes or microglial cells, and an antibody to be tested in a medium.
- the antibody can be directed to the biological entity under test or to an antigen associated with the entity. In the latter situation, the object is to test whether the biological entity is phagocytosed with the antigen.
- the antibody and biological entity are contacted with each other before adding the phagocytic cells.
- the concentration of the biological entity and/or the associated antigen remaining in the medium, if present, is then monitored. A reduction in the amount or concentration of antigen or the associated biological entity in the medium indicates the antibody has a clearing response against the antigen and/or associated biological entity in conjunction with the phagocytic cells.
- an antibody of the invention can be tested for the ability to improve cognition in an appropriate animal model.
- the ability of an antibody to improve cognition in an animal model for AD, as assessed via a contextual fear conditioning (CFC) assay can be used to select the antibody as a candidate for use in the therapeutic methods of the invention, in particular, in methods for effecting rapid improvement in cognition in a patient.
- CFC contextual fear conditioning
- Contextual fear conditioning is a common form of learning that is exceptionally reliable and rapidly acquired in most animals, for example, mammals. Test animals learn to fear a previously neutral stimulus because of its association with an aversive experience and/or environmental cue(s). (see, e.g., Fanselow, Anim. Learn. Behav. 18:264-270 (1990); Wehner et al., Nature Genet. 17:331-334. (1997); Caldarone et al., Nature Genet. 17:335-337 (1997)).
- Contextual fear conditioning is especially useful for determining cognitive function or dysfunction, e.g., as a result of disease or a disorder, such as a neurodegenerative disease or disorder, an A ⁇ -related disease or disorder, an amyloidogenic disease or disorder, the presence of an unfavorable genetic alteration affective cognitive function (e.g., genetic mutation, gene disruption, or undesired genotype), and/or the efficacy of an agent, e.g., an antibody agent, on cognitive ability.
- a disorder such as a neurodegenerative disease or disorder, an A ⁇ -related disease or disorder, an amyloidogenic disease or disorder, the presence of an unfavorable genetic alteration affective cognitive function (e.g., genetic mutation, gene disruption, or undesired genotype)
- an agent e.g., an antibody agent
- the CFC assay provides a method for independently testing and/or validating the therapeutic effect of agents for preventing or treating a cognitive disease or disorder, and in particular, a disease or disorder affecting one or more regions of the brains, e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- a cognitive disease or disorder e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- the CFC assay is performed using standard animal chambers and the employment of conditioning training comprising a mild shock (e.g., 0.35 m foot shock) paired with an auditory (e.g., a period of 85 db white noise), olfactory (e.g., almond or lemon extract), touch (e.g., floor cage texture), and/or visual cue (light flash).
- conditioning training comprises administration of the shock absent a paired cue (i.e., shock associated with context).
- the response to the aversive experience (shock) is typically one of freezing (absence of movement except for respiration) but may also include eye blink, or change in the nictitating membrane reflex, depending on the test animal selected.
- the aversive response is usually characterized on the first day of training to determine a baseline for unconditioned fear with aversive response results on subsequent test days (e.g., freezing in the same context but in the absence of the aversive stimulus and/or freezing in presence of the cue but in the absence of the aversive experience) being characterized as contextually conditioned fear.
- test animals are typically tested separately by independent technicians and scored over time. Additional experimental design details can be found in the art, for example, in Crawley, J N, What's Wrong with my Mouse; Behavioral Phenotyping of Transgenic and Knockout Mice , Wiley-Liss, NY (2000).
- test animals include mammals (e.g. rodents or non-human primates) that exhibit prominent symptoms or pathology that is characteristic of an amyloidogenic disorder such as Alzheimer's.
- Model animals may be created by selective inbreeding for a desired or they may genetically engineered using transgenic techniques that are well-known in the art, such that a targeted genetic alteration (e.g. a genetic mutation, gene disruption) in a gene that is associated with the dementia disorder, leading to aberrant expression or function of the targeted gene.
- a targeted genetic alteration e.g. a genetic mutation, gene disruption
- transgenic mouse strains are available that overexpress APP and develop amyloid plaque pathology and/or develop cognitive deficits that are characteristic of Alzheimer's disease (see for example, Games et al., supra, Johnson-Wood et al., Proc. Natl. Acad. Sci. USA 94:1550 (1997); Masliah E and Rockenstein E. (2000) J Neural Transm Suppl.; 59:175-83).
- the model animal can be created using chemical compounds (e.g. neurotoxins, anaesthetics) or surgical techniques (e.g. stereotactic ablation, axotomization, transection, aspiration) that ablate or otherwise interfere with the normal function of an anatomical brain region (e.g. hippocampus, amygdala, perirhinal cortex, medial septal nucleus, locus coeruleus, mammalary bodies) or specific neurons (e.g. serotonergic, cholinergic, or dopaminergic neurons) that are associated with characteristic symptoms or pathology of the amyloidogenic disorder.
- an anatomical brain region e.g. hippocampus, amygdala, perirhinal cortex, medial septal nucleus, locus coeruleus, mammalary bodies
- specific neurons e.g. serotonergic, cholinergic, or dopaminergic neurons
- the animal model exhibits a prominent cognitive deficit associated with learning or memory in addition to the neurodegenerative pathology that associated with a amyloidogenic disorder. More preferably, the cognitive deficit progressively worsens with increasing age, such that the disease progression in the model animal parallels the disease progression in a subject suffering from the amyloidogenic disorder.
- Conditional fear conditioning and other in vivo assays to test the functionality of the antibodies described herein may be performed using wild-type mice or mice having a certain genetic alteration leading to impaired memory or mouse models of neurodegenerative disease, e.g., Alzheimer's disease, including mouse models which display elevated levels of soluble A ⁇ in the cerebrospinal fluid (CSF) or plasma.
- animal models for Alzheimer's disease include transgenic mice that overexpress the “Swedish” mutation of human amyloid precursor protein (hAPPswe; Tg2576) which show age-dependent memory deficits and plaques (Hsiao et al. (1996) Science 274:99-102).
- the in vivo functionality of the antibodies described herein can also be tested using PDAPP transgenic mice, which express a mutant form of human APP (APP V71F ) and develop Alzheimer's disease at a young age (Bard, et al. (2000) Nature Medicine 6:916-919; Masliah E, et al. (1996) J. Neurosci. 15; 16(18):5795-811).
- Other mouse models for Alzheimer's disease include the PSAPP mouse, a doubly transgenic mouse (PSAPP) overexpressing mutant APP and PS1 transgenes, described in Holcomb, et al. (1998) Nature Medicine 4:97-110, and the PS-1 mutant mouse, described in Duff, et al. (1996) Nature 383, 710-713.
- PSAPP doubly transgenic mouse
- PSAPP a doubly transgenic mouse
- PS-1 mutant mouse described in Duff, et al. (1996) Nature 383, 710-713.
- Other genetically altered transgenic models of Alzheimer's disease are described
- the methods of the invention comprise the administration of an anti-A ⁇ antibody that is capable of rapidly improving cognition in a subject wherein the anti-A ⁇ antibody has been identified in using an assay which is suitably predictive of immunotherapeutic efficacy in the subject.
- the assay is a model animal assay that is based, at least in part, on comparing cognition, as determined from a contextual fear conditioning study, of an animal after administration of a test immunological reagent to the animal, as compared to a suitable control.
- the CFC assay evaluates changes in cognition of an animal (typically a mouse or rat) upon treatment with a potential therapeutic compound.
- the change in cognition evaluated is an improvement in memory impairment status or a reversal of memory deficit.
- the CFC assay provides a direct method for determining the therapeutic effect of agents for preventing or treating cognitive disease, and in particular, a disease or disorder affecting one or more regions of the brains, e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- a disease or disorder affecting one or more regions of the brains e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
- Such CFC assays are discussed further herein and in U.S. Provisional Patent Application Ser. Nos. 60/636,842 filed on Dec. 15, 2004, 60/637,253, filed on Dec. 16, 2004, and 60/736,119, filed on Nov. 10, 2005, the entire content of each
- the effector function of an antibody resides in the constant or Fc region of the molecule which can mediate binding to various effector molecules, e.g., complement proteins or Fc receptors.
- the binding of complement to the Fc region is important, for example, in the opsonization and lysis of cell pathogens and the activation of inflammatory responses.
- the binding of antibody to Fc receptors, for example, on the surface of effector cells can trigger a number of important and diverse biological responses including, for example, engulfment and destruction of antibody-coated pathogens or particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (i.e., antibody-dependent cell-mediated cytotoxicity, or ADCC), release of inflammatory mediators, placental transfer of antibodies, and control of immunoglobulin production.
- killer cells i.e., antibody-dependent cell-mediated cytotoxicity, or ADCC
- the above-mentioned immune functions may be desirable.
- various aspects of the effector function of the molecule including enhancing or suppressing various reactions of the immune system, with beneficial effects in diagnosis and therapy, are achieved.
- the antibodies of the invention can be produced which react only with certain types of Fc receptors, for example, the antibodies of the invention can be modified to bind to only certain Fc receptors, or if desired, lack Fc receptor binding entirely, by deletion or alteration of the Fc receptor binding site located in the Fc region of the antibody.
- Other desirable alterations of the Fc region of an antibody of the invention are cataloged below.
- the EU numbering system ie. the EU index of Kabat et al., supra
- amino acid residue(s) of the Fc region e.g., of an IgG antibody
- the numbering system is also employed to compare antibodies across species such that a desired effector function observed in, for example, a mouse antibody, can then be systematically engineered into a human, humanized, or chimeric antibody of the invention.
- antibodies e.g., IgG antibodies
- Fc receptor e.g., an Fc receptor on human monocytes (Fc ⁇ RI)
- Fc ⁇ RI Fc receptor on human monocytes
- a comparison of the sequence of these proteins in the hinge-link region shows that the sequence from EU numbering positions 234 to 238, i.e., Leu-Leu-Gly-Gly-Pro (SEQ ID NO:32) in the strong binders becomes Leu-Glu-Gly-Gly-Pro (SEQ ID NO:33) in mouse gamma 2b, i.e., weak binders. Accordingly, a corresponding change in a human antibody hinge sequence can be made if reduced Fc ⁇ I receptor binding is desired. It is understood that other alterations can be made to achieve the same or similar results.
- the affinity of Fc ⁇ RI binding can be altered by replacing the specified residue with a residue having an inappropriate functional group on its sidechain, or by introducing a charged functional group (e.g., Glu or Asp) or for example an aromatic non-polar residue (e.g., Phe, Tyr, or Trp).
- a charged functional group e.g., Glu or Asp
- an aromatic non-polar residue e.g., Phe, Tyr, or Trp
- an antibody of the invention is a humanized antibody including amino acid alterations at one or more EU positions 234, 235, 236 and 237.
- a humanized antibody includes amino acid alterations at EU positions 234 and 237 of the hinge link region derived from IgG1 (i.e., L234A and G237A).
- Affinity for other Fc receptors can be altered by a similar approach, for controlling the immune response in different ways.
- the lytic properties of IgG antibodies following binding of the Cl component of complement can be altered.
- the first component of the complement system, Cl comprises three proteins known as Clq, Clr and Cls which bind tightly together. It has been shown that Clq is responsible for binding of the three protein complex to an antibody.
- the Clq binding activity of an antibody can be altered by providing an antibody with an altered CH 2 domain in which at least one of the amino acid residues at EU amino acid positions 318, 320, and 322 of the heavy chain has been changed to a residue having a different side chain.
- suitable alterations for altering, e.g., reducing or abolishing specific C1q-binding to an antibody include changing any one of residues at EU positions 318 (Glu), 320 (Lys) and 322 (Lys), to Ala.
- Clq binding activity can be abolished by replacing any one of the three specified residues with a residue having an inappropriate functionality on its side chain. It is not necessary to replace the ionic residues only with Ala to abolish Clq binding. It is also possible to use other alkyl-substituted non-ionic residues, such as Gly, Ile, Leu, or Val, or such aromatic non-polar residues as Phe, Tyr, Trp and Pro in place of any one of the three residues in order to abolish C1q binding. In addition, it is also be possible to use such polar non-ionic residues as Ser, Thr, Cys, and Met in place of residues 320 and 322, but not 318, in order to abolish Clq binding activity.
- the invention also provides an antibody having an altered effector function wherein the antibody has a modified hinge region.
- the modified hinge region may comprise a complete hinge region derived from an antibody of different antibody class or subclass from that of the CH1 domain.
- the constant domain (CH1) of a class IgG1 antibody can be attached to a hinge region of a class IgG4 antibody.
- the new hinge region may comprise part of a natural hinge or a repeating unit in which each unit in the repeat is derived from a natural hinge region.
- the natural hinge region is altered by converting one or more cysteine residues into a neutral residue, such as alanine, or by converting suitably placed residues into cysteine residues. Such alterations are carried out using art recognized protein chemistry and, preferably, genetic engineering techniques, as described herein.
- the number of cysteine residues in the hinge region of the antibody is reduced, for example, to one cysteine residue.
- This modification has the advantage of facilitating the assembly of the antibody, for example, bispecific antibody molecules and antibody molecules wherein the Fc portion has been replaced by an effector or reporter molecule, since it is only necessary to form a single disulfide bond.
- This modification also provides a specific target for attaching the hinge region either to another hinge region or to an effector or reporter molecule, either directly or indirectly, for example, by chemical means.
- the number of cysteine residues in the hinge region of the antibody is increased, for example, at least one more than the number of normally occurring cysteine residues. Increasing the number of cysteine residues can be used to stabilize the interactions between adjacent hinges. Another advantage of this modification is that it facilitates the use of cysteine thiol groups for attaching effector or reporter molecules to the altered antibody, for example, a radiolabel.
- the invention provides for an exchange of hinge regions between antibody classes, in particular, IgG classes, and/or an increase or decrease in the number of cysteine residues in the hinge region in order to achieve an altered effector function (see for example U.S. Pat. No. 5,677,425 which is expressly incorporated herein).
- a determination of altered antibody effector function is made using the assays described herein or other art recognized techniques.
- the resultant antibody can be subjected to one or more assays to evaluate any change in biological activity compared to the starting antibody.
- the ability of the antibody with an altered Fc region to bind complement or Fc receptors can be assessed using the assays disclosed herein as well as any art recognized assay.
- Production of the antibodies of the invention is carried out by any suitable technique including techniques described herein as well as techniques known to those skilled in the art.
- an appropriate protein sequence e.g. forming part of or all of a relevant constant domain, e.g., Fc region, i.e., CH2, and/or CH3 domain(s), of an antibody, and include appropriately altered residue(s) can be synthesized and then chemically joined into the appropriate place in an antibody molecule.
- genetic engineering techniques are used for producing an altered antibody.
- Preferred techniques include, for example, preparing suitable primers for use in polymerase chain reaction (PCR) such that a DNA sequence which encodes at least part of an IgG heavy chain, e.g., an Fc or constant region (e.g., CH2, and/or CH3) is altered, at one or more residues.
- PCR polymerase chain reaction
- the segment can then be operably linked to the remaining portion of the antibody, e.g., the variable region of the antibody and required regulatory elements for expression in a cell.
- the present invention also includes vectors used to transform the cell line, vectors used in producing the transforming vectors, cell lines transformed with the transforming vectors, cell lines transformed with preparative vectors, and methods for their production.
- the cell line which is transformed to produce the antibody with an altered Fc region is an immortalized mammalian cell line (e.g., CHO cell).
- the cell line used to produce the antibody with an altered Fc region is preferably a mammalian cell line, any other suitable cell line, such as a bacterial cell line or a yeast cell line, may alternatively be used.
- Antibodies (e.g., humanized antibodies) of the invention can be modified for improved function using any of a number of affinity maturation techniques.
- a candidate molecule with a binding affinity to a given target molecule is identified and then further improved or “matured” using mutagenesis techniques resulting in one or more related candidates having a more desired binding interaction with the target molecule.
- the affinity of an antibody is increased.
- antibodies having binding affinities of at least 10 7 M ⁇ 1 , 10 8 M ⁇ 1 or 10 9 M ⁇ 1 can be matured such that their affinities are at least 10 9 M ⁇ 1 , 10 10 M ⁇ 1 or 10 12 M ⁇ 1 .
- One approach for affinity maturing a binding molecule is to synthesize a nucleic acid encoding the binding molecule, or portion thereof, that encodes the desired change or changes.
- Oligonucleotide synthesis is well known in the art and readily automated to produce one or more nucleic acids having any desired codon change(s). Restriction sites, silent mutations, and favorable codon usage may also be introduced in this way.
- one or more codons can be altered to represent a subset of particular amino acids, e.g., a subset that excludes cysteines which can form disulfide linkages, and is limited to a defined region, for example, a CDR region or portion thereof.
- the region may be represented by a partially or entirely random set of amino acids (for additional details, see, e.g., U.S. Pat. Nos. 5,830,650; 5,798,208; 5,824,514; 5,817,483; 5,814,476; 5,723,323; 4,528,266; 4,359,53; 5,840,479; and 5,869,644).
- PCR polymerase chain reaction
- oligonucleotides e.g., primers or single stranded nucleic acids having, e.g., a desired alteration(s)
- Such PCR can also be carried out under conditions that allow for misincorporation of nucleotides to thereby introduce additional variability into the nucleic acids being amplified.
- Non PCR-based methods for performing site directed mutagenesis can also be used and include “Kunkel” mutagenesis that employs single-stranded uracil containing templates and primers that hybridize and introduce a mutation when passed through a particular strain of E. coli (see, e.g., U.S. Pat. No. 4,873,192).
- Additional methods for varying an antibody sequence, or portion thereof include nucleic acid synthesis or PCR of nucleic acids under nonoptimal (i.e., error-prone) conditions, denaturation and renaturation (annealing) of such nucleic acids, exonuclease and/or endonuclease digestion followed by reassembly by ligation or PCR (nucleic acid shuffling), or a combination of one or more of the foregoing techniques as described, for example, in U.S. Pat. Nos.
- antibody libraries comprising a family of candidate antibody molecules having diversity in certain portions of the candidate antibody molecule, e.g., in one or more CDR regions (or a portion thereof), one or more framework regions, and/or one or more constant regions (e.g., a constant region having effector function) can be expressed and screened for desired properties using art recognized techniques (see, e.g., U.S. Pat. Nos. 6,291,161; 6,291,160; 6,291,159; and 6,291,158).
- expression libraries of antibody variable domains having a diversity of CDR3 sequences and methods for producing human antibody libraries having a diversity of CDR3 sequences by introducing, by mutagenesis, a diversity of CDR3 sequences and recovering the library can be constructed (see, e.g., U.S. Pat. No. 6,248,516).
- nucleic acids encoding the candidate antibody molecules can be introduced into cells in an appropriate expression format, e.g., as full length antibody heavy and light chains (e.g., IgG), antibody Fab fragments (e.g., Fab, F(ab′) 2 ), or as single chain antibodies (scFv) using standard vector and cell transfection/transformation technologies (see, e.g., U.S. Pat. Nos. 6,331,415; 6,103,889; 5,260,203; 5,258,498; and 4,946,778).
- full length antibody heavy and light chains e.g., IgG
- antibody Fab fragments e.g., Fab, F(ab′) 2
- scFv single chain antibodies
- Immune responses against amyloid deposits can also be induced by administration of nucleic acids encoding antibodies and their component chains used for passive immunization.
- nucleic acids can be DNA or RNA.
- a nucleic acid segment encoding an immunogen is typically linked to regulatory elements, such as a promoter and enhancer, that allow expression of the DNA segment in the intended target cells of a patient.
- regulatory elements such as a promoter and enhancer
- exemplary promoter and enhancer elements include those from light or heavy chain immunoglobulin genes and/or the CMV major intermediate early promoter and enhancer (Stinski, U.S. Pat. Nos. 5,168,062 and 5,385,839).
- the linked regulatory elements and coding sequences are often cloned into a vector. For administration of double-chain antibodies, the two chains can be cloned in the same or separate vectors.
- a number of viral vector systems are available including retroviral systems (see, e.g., Lawrie and Tumin, Cur. Opin. Genet. Develop. 3:102-109 (1993)); adenoviral vectors (see, e.g., Bett et al., J. Virol. 67:5911 (1993)); adeno-associated virus vectors (see, e.g., Zhou et al., J. Exp. Med.
- viral vectors from the pox family including vaccinia virus and the avian pox viruses, viral vectors from the alpha virus genus such as those derived from Sindbis and Semliki Forest Viruses (see, e.g., Dubensky et al., J. Virol. 70:508 (1996)), Venezuelan equine encephalitis virus (see Johnston et al., U.S. Pat. No. 5,643,576) and rhabdoviruses, such as vesicular stomatitis virus (see Rose, U.S. Pat. No.
- DNA encoding an immunogen can be packaged into liposomes.
- Suitable lipids and related analogs are described by Eppstein et al., U.S. Pat. No. 5,208,036, Felgner et al., U.S. Pat. No. 5,264,618, Rose, U.S. Pat. No. 5,279,833, and Epand et al., U.S. Pat. No. 5,283,185.
- Vectors and DNA encoding an immunogen can also be adsorbed to or associated with particulate carriers, examples of which include polymethyl methacrylate polymers and polylactides and poly (lactide-co-glycolides), see, e.g., McGee et al., J. Micro Encap . (1996).
- Gene therapy vectors or naked polypeptides can be delivered in vivo by administration to an individual patient, typically by systemic administration (e.g., intravenous, intraperitoneal, nasal, gastric, intradermal, intramuscular, subdermal, or intracranial infusion) or topical application (see e.g., Anderson et al., U.S. Pat. No. 5,399,346).
- systemic administration e.g., intravenous, intraperitoneal, nasal, gastric, intradermal, intramuscular, subdermal, or intracranial infusion
- topical application see e.g., Anderson et al., U.S. Pat. No. 5,399,346
- naked polynucleotide refers to a polynucleotide not delivered in association with a transfection facilitating agent. Naked polynucleotides are sometimes cloned in a plasmid vector.
- Such vectors can further include facilitating agents such as bupivacaine (Weiner et al., U.S. Pat. No. 5,593,972).
- DNA can also be administered using a gene gun. See Xiao & Brandsma, supra.
- the DNA encoding an immunogen is precipitated onto the surface of microscopic metal beads.
- the microprojectiles are accelerated with a shock wave or expanding helium gas, and penetrate tissues to a depth of several cell layers.
- the AccelTM Gene Delivery Device manufactured by Agricetus, Inc. Middleton Wis. is suitable.
- naked DNA can pass through skin into the blood stream simply by spotting the DNA onto skin with chemical or mechanical irritation (see Howell et al., WO 95/05853).
- vectors encoding immunogens can be delivered to cells ex vivo, such as cells explanted from an individual patient (e.g., lymphocytes, bone marrow aspirates, tissue biopsy) or universal donor hematopoietic stem cells, followed by reimplantation of the cells into a patient, usually after selection for cells which have incorporated the vector.
- the present invention is directed inter alia to the treatment of A ⁇ -related diseases or disorders, including amyloidogenic disorders and diseases characterized by soluble A ⁇ (e.g. Alzheimer's).
- the invention is also directed to use of the disclosed immunological reagents (e.g., humanized immunoglobulins) in the manufacture of a medicament for the treatment or prevention of an A ⁇ -related disease or disorder or amyloidogenic disease or disorder.
- immunological reagents e.g., humanized immunoglobulins
- the treatment methods of the invention comprise administration of the disclosed immunological reagents (e.g., humanized immunoglobulins against specific epitopes within A ⁇ ) to a patient under conditions that generate a beneficial therapeutic response in a patient (e.g., rapid improvement in cognition, induction of phagocytosis of A ⁇ , reduction of plaque burden, inhibition of plaque formation, reduction of neuritic dystrophy, and/or reversing, treating or preventing cognitive decline) in the patient, for example, for the prevention or treatment of the A ⁇ -related diseases or disorders or amyloidogenic diseases or disorders.
- Such diseases include Alzheimer's disease, Down's syndrome and mild cognitive impairment. The latter can occur with or without other characteristics of an amyloidogenic disease.
- the immunological reagents of the invention may be used to treat any disorder for which treatment with said immunological reagents is shown to provide a therapeutic benefit to a patient suffering from the disorder.
- the disorder may be any cognitive disorder, e.g. a dementia disorder.
- Such cognitive deficits may have a number of origins: a functional mechanism (anxiety, depression), physiological aging (age-associated memory impairment), drugs, or anatomical lesions.
- Indications for which the immunotherapeutic agents of the invention can be useful include learning disabilities or memory deficits due to toxicant exposure, brain injury leading to amnesia, age, schizophrenia, epilepsy, mental retardation, alcoholic blackouts, Korsakoff's syndrome, medication-induced amnesia (e.g. Halcion), basilar artery migraines, or amnesias associated with Herpes simplex encephalitis.
- Some methods of the invention comprise administering an effective dosage of an antibody that specifically binds to a component of an amyloid deposit to the patient. Such methods are particularly useful for preventing or treating Alzheimer's disease in human patients. Exemplary methods comprise administering an effective dosage of an antibody that binds to A ⁇ .
- Preferred methods comprise administering an effective dosage of an antibody that specifically binds to an epitope within residues 1-10 of A ⁇ , for example, antibodies that specifically bind to an epitope within residues 1-3 of A ⁇ , antibodies that specifically bind to an epitope within residues 14 of A ⁇ , antibodies that specifically bind to an epitope within residues 1-5 of A ⁇ , antibodies that specifically bind to an epitope within residues 1-6 of A ⁇ , antibodies that specifically bind to an epitope within residues 1-7 of A ⁇ , or antibodies that specifically bind to an epitope within residues 3-7 of A ⁇ .
- the invention features administering antibodies that bind to an epitope comprising a free N-terminal residue of A ⁇ .
- the invention features administering antibodies that bind to an epitope within residues of 1-10 of A ⁇ wherein residue 1 and/or residue 7 of A ⁇ is aspartic acid. In yet another aspect, the invention features administering antibodies that specifically bind to A ⁇ peptide without binding to full-length amyloid precursor protein (APP).
- the isotype of the antibody is human IgG1. In yet another aspect, the isotype of the antibody is human IgG4.
- a human antibody of the invention is engineered to have an isotype having reduced effector function (e.g., reduced Fc-mediated phagocytosis, reduced ability to opsonize plaques etc.). In a particular embodiment, an antibody of the invention is a humanized 12A11 antibody (e.g., humanized 12A11 v.1) having an IgG4 isotype.
- the invention features administering antibodies that bind to an epitope comprising a free N-terminal residue of A ⁇ . In yet another aspect, the invention features administering antibodies that specifically bind to A ⁇ peptide without binding to full-length amyloid precursor protein (APP). In yet another aspect, the isotype of the antibody is human IgG1. In yet another embodiment, the invention features administering antibodies that bind to and/or capture soluble A ⁇ .
- APP amyloid precursor protein
- the invention features administering antibodies that bind to an amyloid deposit in the patient and induce a clearing response against the amyloid deposit.
- a clearing response can be effected by Fc receptor mediated phagocytosis.
- Such a clearing response can be engineered into an antibody, for example, by including an Fc receptor binding domain (e.g., an IgG2a constant region).
- the methods can be used on both asymptomatic patients and those currently showing symptoms of disease.
- the antibodies used in for passive immunization or immunotherapy of human subjects with A ⁇ -related diseases or disorders or amyloidogenic diseases or disorders can be human, humanized, chimeric or nonhuman antibodies, or fragments thereof (e.g., antigen binding fragments) and can be monoclonal or polyclonal, as described herein.
- the invention features administering an antibody with a pharmaceutical carrier as a pharmaceutical composition.
- the antibody can be administered to a patient by administering a polynucleotide encoding at least one antibody chain. The polynucleotide is expressed to produce the antibody chain in the patient.
- the polynucleotide encodes heavy and light chains of the antibody.
- the polynucleotide is expressed to produce the heavy and light chains in the patient.
- the patient is monitored for level of administered antibody in the blood of the patient.
- the invention features administering an antibody with a pharmaceutical carrier as a pharmaceutical composition.
- the antibody can be administered to a patient by administering a polynucleotide encoding at least one antibody chain.
- the polynucleotide is expressed to produce the antibody chain in the patient.
- the polynucleotide encodes heavy and light chains of the antibody.
- the polynucleotide is expressed to produce the heavy and light chains in the patient.
- the patient is monitored for level of administered antibody in the blood of the patient.
- the invention thus fulfills a longstanding need for therapeutic regimes for preventing or ameliorating the neuropathology and, in some patients, the cognitive impairment associated with an A ⁇ -related disease or disorder or amyloidogenic disease or disorder (e.g., AD).
- AD amyloidogenic disease or disorder
- the present invention provides methods for effecting rapid improvement in cognition in a patient having or at risk for an suffering from an A ⁇ -related disease or disorder or amyloidogenic disease or disorder (e.g., AD).
- the methods feature administering an effective dose of a 12A11 immunological reagent such that rapid improvement in cognition is achieved.
- improvement in one or more cognitive deficits in the patient e.g., procedural learning and/or memory, deficits
- the cognitive deficit can be an impairment in explicit memory (also known as “declarative” or “working” memory), which is defined as the ability to store and retrieve specific information that is available to consciousness and which can therefore be expressed by language (e.g. the ability to remember a specific fact or event).
- the cognitive deficit can be an impairment in procedural memory (also known as “implicit” or “contextual” memory), which is defined as the ability to acquire, retain, and retrieve general information or knowledge that is not available to consciousness and which requires the learning of skills, associations, habits, or complex reflexes to be expressed, e.g. the ability to remember how to execute a specific task.
- procedural memory also known as “implicit” or “contextual” memory
- Individuals suffering from procedural memory deficits are much more impaired in their ability to function normally. As such, treatments which are effective in improving deficits in procedural memory are highly desirable and advantageous.
- the instant invention provides methods for effecting a rapid improvement in cognition in a subject comprising administration of an antibody agent to the subject such that a rapid improvement is achieved within one month after administration of the antibody.
- the rapid improvement in cognition is achieved within one week after administration of the antibody.
- the rapid improvement in cognition is achieved within one day after administration of the antibody.
- the rapid improvement in cognition is achieved within 12 hours after administration of the antibody.
- Patients amenable to treatment include individuals at risk of an A ⁇ -related disease or disorder or amyloidogenic disease or disorder but not showing symptoms, as well as patients presently showing symptoms.
- Alzheimer's disease virtually anyone is at risk of suffering from Alzheimer's disease if he or she lives long enough. Therefore, the present methods can be administered prophylactically to the general population without the need for any assessment of the risk of the subject patient.
- the present methods are especially useful for individuals who are at risk for AD, e.g., those who exhibit exhibit risk factors of AD.
- the main risk factor for AD is increased age. As the population ages, the frequency of AD continues to increase. Current estimates indicate that up to 10% of the population over the age of 65 and up to 50% of the population over the age of 85 have AD.
- AD heritable form of AD
- APP770 e.g., valine 717 to isoleucine (Goate et al., (1991), Nature 349:704); valine 717 to glycine (Chartier et al. (1991) Nature 353:844; Murrell et al.
- AD is not inherited by a patient but develops due to the complex interplay of a variety of genetic factors. These individuals are said to have “sporadic AD” (also known as “late-onset AD”), a form which is much more difficult to diagnose. Nonetheless, the patient population can be screened for the presence of susceptibility alleles or traits that do not cause AD but are known to segregate with AD at a higher frequency than in the general population, e.g., the ⁇ 2, ⁇ 3, and ⁇ 4 alleles of apolipoprotein E (Corder et. al. (1993), Science, 261: 921-923).
- patients lacking the ⁇ 4 allele may be identified as “at risk” for AD.
- patients lacking the ⁇ 4 allele who have relatives who have AD or who suffer from hypercholesterolemia or atherosclerosis may be identified as “at risk” for AD.
- Another potential biomarker is the combined assessment of cerebral spinal fluid (CSF) A ⁇ 42 and tau levels. Low A ⁇ 42 and high tau levels have a predictive value in identifying patients at risk for AD.
- CSF cerebral spinal fluid
- Indicators of patients having probable AD include, but are not limited to, patients (1) having dementia, (2) of an age of 40-90 years old, (3) cognitive deficits, e.g., in two or more cognitive domains, (4) progression of deficits for more than six months, (5) consciousness undisturbed, and/or (6) absence of other reasonable diagnoses.
- MRI three-dimensional magnetic resonance imaging
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- Indicators of patients having probable AD include, but are not limited to, patients (1) having dementia, (2) of an age of 40-90 years old, (3) cognitive deficits, e.g., in two or more cognitive domains, (4) progression of deficits for more than six months, (5) consciousness undisturbed, and/or (6) absence of other reasonable diagnoses.
- AD Alzheimer's disease
- Common symptoms of AD include cognitive deficits that affect the performance of routine skills or tasks, problems with language, disorientation to time or place, poor or decreased judgement, impairments in abstract thought, loss of motor control, mood or behaviour alteration, personality change, or loss of initiative.
- the number deficits or the degree of the cognitive deficit displayed by the patient usually reflects the extent to which the disease has progressed. For example, the patient may exhibit only a mild cognitive impairment, such that the patient exhibits problems with memory (e.g. contextual memory) but is otherwise able to function well.
- the present methods are also useful for individuals who have an A ⁇ -related cognitive deficit, e.g. A ⁇ -related dementia.
- the present methods are especially useful for individuals who have a cognitive deficit or aberrancy caused by or attributed to the presence of soluble oligomeric A ⁇ in the central nervous system (CNS), for example, in the brain or CSF.
- Cognitive deficits caused by or associated with A ⁇ also include those caused by or associated with: (1) the development of ⁇ -amyloid plaques in the brain; (2) abnormal rates of A ⁇ synthesis, processing, degradation or clearance; (3) the formation or activity of soluble oligomeric A ⁇ species (e.g., in the brain); and/or (4) the formation of abnormal forms of A ⁇ .
- AD dementia disorders
- ADAS-Cog Alzheimer's disease Assessment Scale-Cognitive
- the ADAS-Cog is 11-part test that takes 30 minutes to complete.
- the ADAS-Cog is a preferred brief exam for the study of language and memory skills. See Rosen et al. (1984) Am J Psychiatry. 141(11):1356-64; Ihl et al. (2000) Neuropsychobiol. 41(2):102-7; and Weyer et al. (1997) Int Psychogeriatr. 9(2):123-38.
- the Blessed Test is another quick ( ⁇ 10 minute) test of cognition which assesses activities of daily living and memory, concentration and orientation. See captivating et al. (1968) Br J Psychiatry 114(512):797-811.
- CANTAB Cambridge Neuropsychological Test Automated Battery
- the Mini Mental State Exam developed in 1975 by Folestein et al, is a brief test of mental status and cognition function. It does not measure other mental phenomena and is therefore not a substitute for a full mental status examination. It is useful in screening for dementia and its scoring system is helpful in following progress over time.
- the Mini-Mental State Examination MMSE is widely used, with norms adjusted for age and education. It can be used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment. Cognitive assessment of subjects may require formal neuropsychologic testing, with follow-up testing separated by nine months or more (in humans). See Folstein et al.
- the Seven-Minute Screen is a screening tool to help identify patients who should be evaluated for Alzheimer's disease.
- the screening tool is highly sensitive to the early signs of AD, using a series of questions to assess different types of intellectual functionality.
- the test consists of 4 sets of questions that focus on orientation, memory, visuospatial skills and expressive language. It can distinguish between cognitive changes due to the normal aging process and cognitive deficits due to dementia. See Solomon and Pendlebury (1998) Fam Med. 30(4):265-71, Solomon et al. (1998) Arch Neurol. 55(3):349-55.
- Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above.
- a number of diagnostic tests are available for identifying individuals who have AD. These include measurement of CSF tau and A ⁇ 42 levels. Elevated tau and decreased A ⁇ 42 levels signify the presence of AD.
- Individuals suffering from Alzheimer's disease can also be diagnosed by ADRDA criteria as discussed in the Examples section.
- compositions or medicaments are administered to a patient susceptible to, or otherwise at risk of, Alzheimer's disease in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the outset of the disease, including biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
- compositions or medicaments are administered to a patient suspected of, or already suffering from such a disease in an amount sufficient to cure, or at least partially arrest, the symptoms of the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes in development of the disease.
- reagent reduces or eliminates myocognitive impairment in patients that have not yet developed characteristic Alzheimer's pathology.
- An amount adequate to accomplish therapeutic or prophylactic treatment is defined as a therapeutically- or prophylactically-effective dose.
- reagents are usually administered in several dosages until a sufficient immune response has been achieved.
- immuno response or “immunological response” includes the development of a humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a recipient subject.
- Such a response can be an active response, i.e., induced by administration of immunogen, or a passive response, i.e., induced by administration of immunoglobulin or antibody or primed T-cells.
- a passive response i.e., induced by administration of immunoglobulin or antibody or primed T-cells.
- the immune response is monitored and repeated dosages are given if the immune response starts to wane.
- Effective doses of the compositions of the present invention, for the treatment of the above described conditions vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
- the patient is a human but non-human mammals including transgenic mammals can also be treated. Treatment dosages need to be titrated to optimize safety and efficacy.
- the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg (e.g., 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 2 mg/kg, etc.), of the host body weight.
- dosages can be 1 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg, preferably at least 1 mg/kg.
- dosages can be 0.5 mg/kg body weight or 15 mg/kg body weight or within the range of 0.5-15 mg/kg, preferably at least 1 mg/kg.
- dosages can be 0.5 mg/kg body weight or 20 mg/kg body weight or within the range of 0.5-20 mg/kg, preferably at least 1 mg/kg. In another example, dosages can be 0.5 mg/kg body weight or 30 mg/kg body weight or within the range of 0.5-30 mg/kg, preferably at least 1 mg/kg. In a preferred example, dosages can be about 30 kg/mg. In a particularly preferred example, the 12A11 antibody is administered intraperitoneally at a dose range from approximately 0.3 mg/kg to approximately 30 mg/kg.
- the methods of the invention comprise the administration of an antibody agent (e.g. an A ⁇ antibody) to a subject as a single dose. In other embodiments, the methods of the invention comprise the administration of an antibody agent (e.g. an A ⁇ antibody) to a subject in multiple doses.
- the dose of A ⁇ antibody is from about 100 ⁇ g/kg to 100 mg/kg body weight of the patient. In another embodiment, the dose of A ⁇ antibody is from about 300 ⁇ g/kg to 30 mg/kg body weight of the patient. In still another embodiment, the dose of A ⁇ antibody is from about 1 mg/kg to 10 mg/kg body weight of the patient.
- Doses intermediate in the above ranges are also intended to be within the scope of the invention.
- Subjects can be administered such doses daily, on alternative days, weekly or according to any other schedule determined by empirical analysis.
- An exemplary treatment involves administration in multiple dosages over a prolonged period, for example, of at least six months. Additional exemplary treatment regimes involve administration once per every two weeks or once a month or once every 3 to 6 months.
- Exemplary dosage schedules include 1-10 mg/kg or 15 mg/kg on consecutive days, 30 mg/kg on alternate days or 60 mg/kg weekly.
- two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage, of each antibody administered falls within the ranges indicated.
- Antibody is usually administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to A ⁇ in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of 1-1000 ⁇ g/ml and in some methods 25-300 ⁇ g/ml. Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, humanized antibodies show the longest half-life, followed by chimeric antibodies and nonhuman antibodies.
- compositions containing the present antibodies or a cocktail thereof are administered to a patient not already in the disease state to enhance the patient's resistance. Such an amount is defined to be a “prophylactic effective dose.”
- prophylactic effective dose the precise amounts again depend upon the patient's state of health and general immunity, but generally range from 0.1 to 25 mg per dose, especially 0.5 to 2.5 mg per dose.
- a relatively low dosage is administered at relatively infrequent intervals over a long period of time.
- treatment can begin at any age (e.g., 10, 20, 30). Usually, however, it is not necessary to begin treatment until a patient reaches 40, 50, 60 or 70. Treatment typically involves multiple dosages over a period of time. Treatment can be monitored by assaying antibody levels over time. If the response falls, a booster dosage is indicated. In the case of potential Down's syndrome patients, treatment can begin antenatally by administering therapeutic reagent to the mother or shortly after birth.
- a relatively high dosage e.g., from about 1 to 200 mg of antibody per dose, with dosages of from 5 to 25 mg being more commonly used
- a relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patent can be administered a prophylactic regime.
- Doses for nucleic acids encoding antibodies range from about 10 ng to 1 g, 100 ng to 100 mg, 1 ⁇ g to 10 mg, or 30-300 ⁇ g DNA per patient.
- Doses for infectious viral vectors vary from 10-100, or more, virions per dose.
- Therapeutic reagents can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intracranial, intraperitoneal, intranasal or intramuscular means for prophylactic and/or therapeutic treatment.
- the most typical route of administration of an immunogenic agent is subcutaneous although other routes can be equally effective.
- the next most common route is intramuscular injection. This type of injection is most typically performed in the arm or leg muscles.
- reagents are injected directly into a particular tissue where deposits have accumulated, for example intracranial injection. Intramuscular injection or intravenous infusion are preferred for administration of antibody.
- particular therapeutic antibodies are injected directly into the cranium.
- antibodies are administered as a sustained release composition or device, such as a MedipadTM device.
- Immunological reagents of the invention can optionally be administered in combination with other agents that are at least partly effective in treatment of amyloidogenic disease.
- a humanized antibody of the invention e.g., humanized 12A11
- a second immunogenic or immunologic reagent e.g., a humanized 12A11 antibody of the invention is administered in combination with another humanized antibody to A ⁇ .
- a humanized 12A11 antibody is administered to a patient who has received or is receiving an A ⁇ vaccine.
- agents of the invention can also be administered in conjunction with other agents that increase passage of the agents of the invention across the blood-brain barrier.
- Immunological reagents of the invention can also be administered in combination with other agents that enhance access of the therapeutic agent to a target cell or tissue, for example, liposomes and the like. Coadministering such agents can decrease the dosage of a therapeutic agent (e.g., therapeutic antibody or antibody chain) needed to achieve a desired effect.
- a therapeutic agent e.g., therapeutic antibody or antibody chain
- Immunological regents of the invention are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa. (1980)). The preferred form depends on the intended mode of administration and therapeutic application.
- the compositions can also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination.
- compositions or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
- compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized SepharoseTM, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes). Additionally, these carriers can function as immunostimulating agents (i.e., adjuvants).
- agents of the invention can be administered as injectable dosages of a solution or suspension of the substance in a physiologically acceptable diluent with a pharmaceutical carrier that can be a sterile liquid such as water oils, saline, glycerol, or ethanol.
- a pharmaceutical carrier that can be a sterile liquid such as water oils, saline, glycerol, or ethanol.
- auxiliary substances such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions.
- Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
- glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
- Antibodies can be administered in the form of a depot injection or implant preparation, which can be formulated in such a manner as to permit a sustained release of the active ingredient.
- An exemplary composition comprises monoclonal antibody at 5 mg/mL, formulated in aqueous buffer consisting of 50 mM L-histidine, 150 mM NaCl, adjusted to pH 6.0 with HCl.
- compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared.
- the preparation also can be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above (see Langer, Science 249: 1527 (1990) and Hanes, Advanced Drug Delivery Reviews 28:97 (1997)).
- the agents of this invention can be administered in the form of a depot injection or implant preparation, which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
- binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%.
- Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10%-95% of active ingredient, preferably 25%-70%.
- Topical application can result in transdermal or intradermal delivery.
- Topical administration can be facilitated by co-administration of the agent with cholera toxin or detoxified derivatives or subunits thereof or other similar bacterial toxins (See Glenn et al., Nature 391, 851 (1998)).
- Co-administration can be achieved by using the components as a mixture or as linked molecules obtained by chemical crosslinking or expression as a fusion protein.
- transdermal delivery can be achieved using a skin patch or using transferosomes (Paul et al., Eur. J. Immunol. 25:3521 (1995); Cevc et al., Biochem. Biophys. Acta 1368:201-15 (1998)).
- the invention provides methods of monitoring treatment in a patient suffering from or susceptible to Alzheimer's, i.e., for monitoring a course of treatment being administered to a patient.
- the methods can be used to monitor both therapeutic treatment on symptomatic patients and prophylactic treatment on asymptomatic patients.
- the methods are useful for monitoring passive immunization (e.g., measuring level of administered antibody).
- Some methods involve determining a baseline value, for example, of an antibody level or profile in a patient, before administering a dosage of agent, and comparing this with a value for the profile or level after treatment.
- a significant increase i.e., greater than the typical margin of experimental error in repeat measurements of the same sample, expressed as one standard deviation from the mean of such measurements
- a positive treatment outcome i.e., that administration of the agent has achieved a desired response. If the value for immune response does not change significantly, or decreases, a negative treatment outcome is indicated.
- a control value i.e., a mean and standard deviation
- a control value i.e., a mean and standard deviation
- Measured values of the level or profile in a patient after administering a therapeutic agent are then compared with the control value.
- a significant increase relative to the control value e.g., greater than one standard deviation from the mean
- a lack of significant increase or a decrease signals a negative or insufficient treatment outcome.
- Administration of agent is generally continued while the level is increasing relative to the control value. As before, attainment of a plateau relative to control values is an indicator that the administration of treatment can be discontinued or reduced in dosage and/or frequency.
- a control value of the level or profile (e.g., a mean and standard deviation) is determined from a control population of individuals who have undergone treatment with a therapeutic agent and whose levels or profiles have plateaued in response to treatment. Measured values of levels or profiles in a patient are compared with the control value. If the measured level in a patient is not significantly different (e.g., more than one standard deviation) from the control value, treatment can be discontinued. If the level in a patient is significantly below the control value, continued administration of agent is warranted. If the level in the patient persists below the control value, then a change in treatment may be indicated.
- a control value of the level or profile e.g., a mean and standard deviation
- a patient who is not presently receiving treatment but has undergone a previous course of treatment is monitored for antibody levels or profiles to determine whether a resumption of treatment is required.
- the measured level or profile in the patient can be compared with a value previously achieved in the patient after a previous course of treatment. A significant decrease relative to the previous measurement (i.e., greater than a typical margin of error in repeat measurements of the same sample) is an indication that treatment can be resumed.
- the value measured in a patient can be compared with a control value (mean plus standard deviation) determined in a population of patients after undergoing a course of treatment.
- the measured value in a patient can be compared with a control value in populations of prophylactically treated patients who remain free of symptoms of disease, or populations of therapeutically treated patients who show amelioration of disease characteristics.
- a significant decrease relative to the control level i.e., more than a standard deviation is an indicator that treatment should be resumed in a patient.
- the tissue sample for analysis is typically blood, plasma, serum, mucous fluid or cerebrospinal fluid from the patient.
- the sample is analyzed, for example, for levels or profiles of antibodies to A ⁇ peptide, e.g., levels or profiles of humanized antibodies.
- ELISA methods of detecting antibodies specific to A ⁇ are described in the Examples section.
- the level or profile of an administered antibody is determined using a clearing assay, for example, in an in vitro phagocytosis assay, as described herein.
- a tissue sample from a patient being tested is contacted with amyloid deposits (e.g., from a PDAPP mouse) and phagocytic cells bearing Fc receptors. Subsequent clearing of the amyloid deposit is then monitored.
- the existence and extent of clearing response provides an indication of the existence and level of antibodies effective to clear A ⁇ in the tissue sample of the patient under test.
- the antibody profile following passive immunization typically shows an immediate peak in antibody concentration followed by an exponential decay. Without a further dosage, the decay approaches pretreatment levels within a period of days to months depending on the half-life of the antibody administered.
- a baseline measurement of antibody to A ⁇ in the patient is made before administration, a second measurement is made soon thereafter to determine the peak antibody level, and one or more further measurements are made at intervals to monitor decay of antibody levels.
- a predetermined percentage of the peak less baseline e.g., 50%, 25% or 10%
- administration of a further dosage of antibody is administered.
- peak or subsequent measured levels less background are compared with reference levels previously determined to constitute a beneficial prophylactic or therapeutic treatment regime in other patients. If the measured antibody level is significantly less than a reference level (e.g., less than the mean minus one standard deviation of the reference value in population of patients benefiting from treatment) administration of an additional dosage of antibody is indicated.
- Additional methods include monitoring, over the course of treatment, any art-recognized physiologic symptom (e.g., physical or mental symptom) routinely relied on by researchers or physicians to diagnose or monitor amyloidogenic diseases (e.g., Alzheimer's disease).
- physiologic symptom e.g., physical or mental symptom
- amyloidogenic diseases e.g., Alzheimer's disease
- cognitive impairment can be monitored by determining a patient's score on the Mini-Mental State Exam in accordance with convention throughout the course of treatment.
- kits for performing the monitoring methods described above.
- such kits contain an agent that specifically binds to antibodies to A ⁇ .
- the kit can also include a label.
- the label is typically in the form of labeled anti-idiotypic antibodies.
- the agent can be supplied prebound to a solid phase, such as to the wells of a microtiter dish.
- Kits also typically contain labeling providing directions for use of the kit.
- the labeling may also include a chart or other correspondence regime correlating levels of measured label with levels of antibodies to A ⁇ .
- labeling refers to any written or recorded material that is attached to, or otherwise accompanies a kit at any time during its manufacture, transport, sale or use.
- the term labeling encompasses advertising leaflets and brochures, packaging materials, instructions, audio or videocassettes, computer discs, as well as writing imprinted directly on kits.
- kits for example, research, detection and/or diagnostic kits (e.g., for performing in vivo imaging).
- diagnostic kits typically contain an antibody for binding to an epitope of A ⁇ , preferably within residues 1-10.
- the antibody is labeled or a secondary labeling reagent is included in the kit.
- the kit is labeled with instructions for performing the intended application, for example, for performing an in vivo imaging assay. Exemplary antibodies are those described herein.
- the invention provides methods of in vivo imaging amyloid deposits in a patient. Such methods are useful to diagnose or confirm diagnosis of Alzheimer's disease, or susceptibility thereto. For example, the methods can be used on a patient presenting with symptoms of dementia. If the patient has abnormal amyloid deposits, then the patient is likely suffering from Alzheimer's disease. The methods can also be used on asymptomatic patients. Presence of abnormal deposits of amyloid indicates susceptibility to future symptomatic disease. The methods are also useful for monitoring disease progression and/or response to treatment in patients who have been previously diagnosed with Alzheimer's disease.
- the methods work by administering a reagent, such as antibody that binds to A ⁇ , to the patient and then detecting the agent after it has bound.
- a reagent such as antibody that binds to A ⁇
- Preferred antibodies bind to A ⁇ deposits in a patient without binding to full length APP polypeptide.
- Antibodies binding to an epitope of A ⁇ within amino acids 1-10 are particularly preferred.
- the antibody binds to an epitope within amino acids 7-10 of A ⁇ .
- Such antibodies typically bind without inducing a substantial clearing response.
- the antibody binds to an epitope within amino acids 1-7 of A ⁇ .
- Such antibodies typically bind and induce a clearing response to A ⁇ .
- the clearing response can be avoided by using antibody fragments lacking a full-length constant region, such as Fabs.
- the same antibody can serve as both a treatment and diagnostic reagent.
- antibodies binding to epitopes C-terminal to residue 10 of A ⁇ do not show as strong a signal as antibodies binding to epitopes within residues 1-10, presumably because the C-terminal epitopes are inaccessible in amyloid deposits. Accordingly, such antibodies are less preferred.
- Diagnostic reagents can be administered by intravenous injection into the body of the patient, or directly into the brain by intracranial injection or by drilling a hole through the skull.
- the dosage of reagent should be within the same ranges as for treatment methods.
- the reagent is labeled, although in some methods, the primary reagent with affinity for A ⁇ is unlabelled and a secondary labeling agent is used to bind to the primary reagent.
- the choice of label depends on the means of detection. For example, a fluorescent label is suitable for optical detection. Use of paramagnetic labels is suitable for tomographic detection without surgical intervention. Radioactive labels can also be detected using PET or SPECT.
- Diagnosis is performed by comparing the number, size, and/or intensity of labeled loci, to corresponding baseline values.
- the base line values can represent the mean levels in a population of undiseased individuals. Baseline values can also represent previous levels determined in the same patient. For example, baseline values can be determined in a patient before beginning treatment, and measured values thereafter compared with the baseline values. A decrease in values relative to baseline signals a positive response to treatment.
- a single-dose phase I trial can be performed to determine safety in humans.
- a therapeutic agent e.g., an antibody of the invention
- a therapeutic agent is administered in increasing dosages to different patients starting from about 0.01 the level of presumed efficacy, and increasing by a factor of three until a level of about 10 times the effective mouse dosage is reached.
- a phase II trial can further performed to determine therapeutic efficacy.
- Patients with early to mid Alzheimer's Disease defined using Alzheimer's disease and Related Disorders Association (ADRDA) criteria for probable AD are selected. Suitable patients score in the 12-26 range on the Mini-Mental State Exam (MMSE). Other selection criteria are that patients are likely to survive the duration of the study and lack complicating issues such as use of concomitant medications that may interfere.
- Baseline evaluations of patient function are made using classic psychometric measures, such as the MMSE, and the ADAS, which is a comprehensive scale for evaluating patients with Alzheimer's Disease status and function. These psychometric scales provide a measure of progression of the Alzheimer's condition. Suitable qualitative life scales can also be used to monitor treatment. Disease progression can also be monitored by MRI. Blood profiles of patients can also be monitored including assays of immunogen-specific antibodies and T-cells responses.
- patients Following baseline measurements, patients begin receiving treatment. They are randomized and treated with either therapeutic agent or placebo in a blinded fashion. Patients are monitored at least every six months. Efficacy is determined by a significant reduction in progression of a treatment group relative to a placebo group.
- a second phase II trial can be performed to evaluate conversion of patients from non-Alzheimer's Disease early memory loss, sometimes referred to as age-associated memory impairment (AAMI) or mild cognitive impairment (MCI), to probable Alzheimer's disease as defined as by ADRDA criteria.
- Patients with high risk for conversion to Alzheimer's Disease are selected from a non-clinical population by screening reference populations for early signs of memory loss or other difficulties associated with pre-Alzheimer's symptomatology, a family history of Alzheimer's Disease, genetic risk factors, age, sex, and other features found to predict high-risk for Alzheimer's Disease.
- Baseline scores on suitable metrics including the MMSE and the ADAS together with other metrics designed to evaluate a more normal population are collected.
- patient populations are divided into suitable groups with placebo comparison against dosing alternatives with the agent. These patient populations are followed at intervals of about six months, and the endpoint for each patient is whether or not he or she converts to probable Alzheimer's Disease as defined by ADRDA criteria at the end of the observation.
- an antibody or immunoglobulin sequence comprising a VL and/or VH sequence as set forth in any one of SEQ ID NOs:1-4, 7, 10, 13-31, and 34-37 can comprise either the full sequence or can comprise (or encode) the mature sequence (i.e., mature peptide without the signal or leader peptide).
- Binding of monoclonal antibody 12A11 to aggregated synthetic A ⁇ 1-42 was performed by ELISA, as described in Schenk, et al. ( Nature 400:173 (1999)). For comparison purposes, mAbs 12B4, and 10D5 were also assayed.
- Soluble A ⁇ 1-42 refers to the synthetic A ⁇ 1142 peptide sonicated in dimethyl sulfoxide (DMSO). Serial dilutions of the antibodies at 20 ⁇ g/ml were incubated with 50,000 cpm [ 125 I]A ⁇ 1-42 (190 ⁇ Ci/ ⁇ mol; labeling with Iodogen reagent, Pierce) overnight at room temperature.
- antibodies 12B4 and 12A11 appreciably captured soluble A ⁇ 1-42 at antibody concentrations of 20 ⁇ g/ml. As shown in Table 2, the IgG1 antibody 12A1 captured A ⁇ 1-42 more efficiently than the IgG2a antibody 12B4 or the IgG1 antibody 10D5.
- the ability of various antibodies (including 12A11) to capture soluble A ⁇ was further assayed as follows. Various concentrations of antibody (up to 10 ⁇ g/ml) were incubated with 50,000 CPM of 125 I-A ⁇ 1-42 (or 125 I-A ⁇ 1-40). The concentration of antibody sufficient to bind 25% of the radioactive counts was determined in a capture radioimmunoassay. For antibodies not capable of binding 25% of the counts at 10 ⁇ g/ml, the percentage of counts bound at 10 ⁇ g/ml was determined. The 12A11 bound 20% of the radioactive counts (i.e., 125 I-A ⁇ ) at 10 ⁇ g/ml.
- the 12B4 antibody reduced A ⁇ levels efficiently (73% for 12B4; P ⁇ 0.001) with 12A11 showing somewhat less, albeit statistically significant, efficiency (48% for 12A11, P ⁇ 0.05).
- the 10D5 antibody did not significantly reduce A ⁇ levels.
- the performance of 12A11 in the ex vivo phagocytosis assay may be improved upon conversion to the IgG2a isotype which is a preferred isotype for microglial phagocytosis.
- Mouse Antibody 12A11 Reduces Alzheimer's-Like Neuropathology In Vivo To determine the in vivo efficacy of 12A11, antibodies (including 12A11, 12B4, or 10D5) were administered to mice at 10 mg/kg by weekly intraperitoneal injection for 6 months as described in Bard et al. (2000) Nat. Med. 6:916. At the end of the study, total levels of cortical A ⁇ were determined by ELISA. As shown in FIG. 2A , each of the antibodies significantly reduced total A ⁇ levels compared with the PBS control (P ⁇ 0.001), i.e. 12B4 showed a 69% reduction, 10D5 showed a 52% reduction, and 12A11 showed a 31% reduction.
- the level of neuritic dystrophy was then examined in sections of brain tissue from the above-mentioned mice to determine the association between plaque clearance and neuronal protection.
- Data from brain image analyses examining the percentage of frontal cortex occupied by neurotic dystrophy is shown in FIG. 2B .
- These data show that antibodies 10D5 and 12A11 were not effective at reducing neuritic dystrophy whereas 12B4 significantly reduced neuritic dystrophy (12B4, P ⁇ 0.05; ANOVA followed by post hoc Dunnett's test), as determined by the assay described herein. Again, this activity of 12A11 may be improved by converting 12A11 to the IgG2a isotype (murine efficacy).
- IgG1 isotypes are preferred for reducing neuritic dystrophy.
- the IgG2a isotype (affinity for Fc receptors, in particular, Fc ⁇ RI) appears to be an important attribute for both clearance of A ⁇ and protection against neuritic dystrophy.
- the antibody 12A11 (IgG1) captured soluble monomeric A ⁇ 1-42 more efficiently than 12B4 (IgG2a) or 10D5 (IgG1) but was not as effective at reducing neuritic dystrophy.
- Enhanced efficacy in reducing plaque burden and reducing neuritic dystrophy may be achieved by engineering antibodies to have an isotype which maximally supports phagocytosis. Particularly efficacious antibodies bind to epitopes within the N terminus of A ⁇ .
- a 12A11 IgG2a isotype antibody was tested for the ability to reduce AD-like neuropathology in PDAPP mice. 12-13 month old PDAPP mice were injected weekly for 6 months with 3 mg/kg 12A11 antibody. At the end of six months, animals were sacrificed and brain samples were analyzed for various end points including, AB burden, neuritic burden and synaptophysin levels. Administration of 12A11 antibody significantly reduced the level of amyloid burden in PDAPP brain samples. Administration of 12A11 antibodies also significantly reduced the degree of neuritic dystrophy (abnormal neuronal processes surrounding plaques). In addition, 12A11 administration significantly protected against the loss of synaptophysin (measure of synaptic integrity).
- This example demonstrates the ability of various A ⁇ antibodies to preferentially bind to soluble, oligomeric A ⁇ .
- the data are used to predict the therapeutic efficacy of the A ⁇ antibodies.
- the A ⁇ preparation was prepared from synthetic A ⁇ substantially as follows:
- test immunological reagent in this case antibodies
- a ⁇ monomers and one or more A ⁇ oligomers which bound to the test immunological reagent were extracted from the A ⁇ preparation by immunoprecipitation.
- the various immunoprecipitates were separated by gel electrophoresis and immunoblotted (imaged) with the 3D6 antibody substantially as follows.
- Immunoprecipitate samples of FIGS. 3-4 were diluted in sample buffer and separated by SDS-PAGE on a 16% Tricine gel. The protein was transferred to nitrocellulose membranes, the membranes boiled in PBS, and then blocked overnight at 4° C. in a solution of TBS/Tween/5% Carnation dry milk.
- the membranes were then incubated with 3D6, a mouse monoclonal A ⁇ antibody to residues 1-5.
- the membranes were incubated with anti-mouse Ig-HRP, developed using ECL PlusTM, and visualized using film.
- Molecular mass was estimated by SeeBlue Plus2TM molecular weight markers.
- FIGS. 3-4 depict the results of contacting the above A ⁇ 1-42 preparations with various test immunological reagents (in FIGS. 3-4 A ⁇ antibodies) to determine the binding of, e.g., A ⁇ monomers, dimers, trimers, tetramers, pentamers, etc. in the A ⁇ preparation to the test immunological reagent.
- FIGS. 3-4 depict Western blots (imaged with 3D6) of immunoprecipitates of a peroxynitrite treated oligomeric A ⁇ preparation contacted with various A ⁇ antibodies. The approximate positions of A ⁇ 1-42 monomer, dimer, trimer and tetramer bands are indicated on the left-hand side of each figure.
- each A ⁇ antibody is the A ⁇ epitope recognized by the antibody and CFC assay results (see Example V, supra) for the antibody
- a “+” notation indicates an observation of increased cognition upon treatment with the antibody
- a “ ⁇ ” notation indicates an observation of no change in cognition upon treatment with the antibody
- a “+/ ⁇ ” notation indicates an observation of a trend of increased cognition upon treatment with the antibody but which is not statistically significant enough to be indicated as an observation of increased cognition
- “ND” notation indicates no CFC assay data available or compared for this antibody.
- a ⁇ antibodies 3D6, 15C11, 10D5, 12A11 and 266 exhibited preferential binding for oligomeric A ⁇ species as compared to monomeric A ⁇ with 12A11 exhibiting the most significant preferential binding to oligomeric A ⁇ . Accordingly, these antibodies are predicted to have therapeutic efficacy in the treatment cognitive deficits, e.g., those associated with AD.
- Wild-type and Tg2576 mice were administered a single dose of phosphate buffered saline (PBS) or treatment antibody by intraperitoneal injection.
- PBS phosphate buffered saline
- each mouse was administered a CFC training session immediately following treatment and a CFC testing session within 24 hours of treatment (i.e. Day 1 post-treatment).
- Therapeutic efficacy was expressed both in terms of memory deficit reversal and memory impairment status. “Memory deficit reversal” was determined by comparing the freezing behavior of mAb-vs. PBS control-treated Tg2576 animals. “Memory impairment status” was determined by comparing the freezing behavior of Wild-type vs. Tg2576 mAb-treated animals.
- the therapeutic efficacy of several mAbs raised against the N-terminus of A ⁇ are tabulated in Table 3.
- the results of the CFC testing session conducted on Day 1 post-treatment indicate that the mAbs 3D6, 10D5, and 12A11 caused a rapid and significant (**) improvement in contextual memory of Tg2576 mice relative to a control treatment (p value ⁇ 0.05).
- 3D6, 10D5, and 12A11-treated Tg2576 mice had no significant memory impairment (##) with respect to wild-type mice (p value >0.1).
- the antibodies 6C6, 10D5, and 12B4 displayed a trend towards effecting either memory deficit reversal (*) or no memory impairment (#) (0.1>p value>0.05).
- Tg2576 mice displayed a particularly prominent, significant, and rapid improvement in contextual memory when administered the N-terminal, murine IgG2a mAb designated 12A11.
- the 12A11 resulted in a memory deficit reversal at every dose tested (0.3, 1, 10, or 30 mg/kg) [see FIGS. 5A and 5B ].
- untreated (PBS) Tg2576 mice displayed a significant deficit in contextual-dependent memory (*) in comparison with wild-type mice [ FIG. 5A ].
- Tg2576 mice exhibited a full and significant memory deficit reversal (#) when administered 1, 10, or 30 mg/kg (i.p.) of 12A11. The improvement in cognitive performance persisted when mice were administered lower doses (0.1 and 1 mg/kg i.p.) of 12A11 [ FIG. 5B ].
- Tg2576 mice were administered 30 mg/kg of IgG2a isotype control mAb raised against an unrelated antigen from E. tennela .
- Tg2576 mice treated with the control antibody exhibited profound defects in contextual memory in relation to wild-type mice.
- mice Tg2575 and wild-type mice were again administered a PBS control or a low dose of 12A11 antibody (1 mg/kg ip) and their cognitive status was assessed by CFC assay on Day 0-1, 9-10, and 16-17 post-treatment (i.e. with the CFC training sessions performed on Days 0, 9, 16 and CFC testing sessions performed on Days 1, 10, and 17).
- Tg2576 mice again displayed prominent, significant, and rapid improvement in contextual memory on Day 1 following treatment with mu12A11 [see FIG. 6 ].
- Tg2576 treated with mu12A11 exhibited a significant memory deficit reversal (when compared with PBS-treated Tg2576 mice and memory impairment status that approached parity with that of wild-type mice.
- These improvements in contextual memory persisted and were even more pronounced when assessed at Day 10 post-treatment.
- mu12A11 continued to display a trend towards no memory impairment.
- VH and VL regions of 12A11 from hybridoma cells were cloned by RT-PCR and 5′ RACE using mRNA from hybridoma cells and standard cloning methodology.
- the nucleotide sequence (coding, SEQ ID NO:3) and deduced amino acid sequence (SEQ ID NO:4) derived from independent cDNA clones encoding the presumed mu12A11 VH domain, are set forth in Table 6 and Table 7, respectively (see also FIG. 7B ).
- the light chain variable VL region of 12A11 was cloned in an analogous manner as the VH region.
- the nucleotide sequence (coding, SEQ ID NO:1) and deduced amino acid sequence (SEQ ID NO:2) derived from two independent cDNA clones encoding the presumed 12A11 VL domain, are set forth in Table 8 and Table 9, respectively (see also FIG. 7A ).
- both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- variable heavy and light chain regions were re-engineered to encode splice donor sequences downstream of the respective VDJ or VJ junctions, and cloned into the mammalian expression vector pCMV-h ⁇ 1 for the heavy chain (SEQ ID NOs:57 and 58), and pCMV-h ⁇ 1 (SEQ ID NOs:59 and 60) for the light chain (see e.g., Maeda et al. (1991) Hum. Antibod. Hybridomas. 2:124-134). These vectors encode human ⁇ 1 and Ck constant regions as exonic fragments downstream of the inserted variable region cassette. Following sequence verification, the heavy chain and light chain expression vectors were co-transfected into COS cells.
- FIG. 8 demonstrates that chimeric 12A11 was found to bind to A ⁇ with high avidity, similar to that demonstrated by chimeric and humanized 3D6.
- the cloning, characterization and humanization of 3D6 is described in U.S. patent application Ser. No. 10/010,942, the entire content of which is incorporated herein by this reference.
- Binding avidity was also similar to that demonstrated by chimeric and humanized 12B4.
- the cloning, characterization and humanization of 12B4 is described in U.S. patent application Ser. No. 10/388,214, the entire content of which is incorporated herein by this reference.
- Suitable human acceptor antibody sequences were identified by computer comparisons of the amino acid sequences of the mouse variable regions with the sequences of known human antibodies. The comparison was performed separately for the 12A11 heavy and light chains.
- variable domains from human antibodies whose framework sequences exhibited a high degree of sequence identity with the murine VL and VH framework regions were identified by query of the NCBI Ig Database using NCBI BLAST (publicly accessible through the National Institutes of Health NCBI internet server) with the respective murine framework sequences.
- the selected acceptor sequence for VL is BAC01733 (SEQ ID NO: 8) in the NCBI Ig non-redundant database.
- the selected acceptor sequence for VH is AAA69734 (SEQ ID NO: 11) in the NCBI Ig non-redundant database.
- AAA69734 (SEQ ID NO: 11) is a human subgroup III antibody (rather than subgroup II) but was selected as an initial acceptor antibody based at least in part on the reasoning in Saldanha et al. (1999) Mol. Immunol. 36:709.
- First versions of humanized 12A11 antibody utilize these selected acceptor antibody sequences. The antibody is described in Schroeder and Wang (1990) Proc. Natl. Acad. Sci. USA 872:6146.
- the humanized antibodies of the invention comprise variable framework regions substantially from a human immunoglobulin (acceptor immunoglobulin) and complementarity determining regions substantially from a mouse immunoglobulin (donor immunoglobulin) termed 12A11. Having identified the complementarity determining regions of 12A11 and appropriate human acceptor immunoglobulins, the next step was to determine which, if any, residues from these components to substitute to optimize the properties of the resulting humanized antibody.
- the amino acid alignment of the reshaped light chain V region is shown in FIG. 9A .
- the choice of the acceptor framework (BAC01733 (SEQ ID NO: 8)) is from the same human subgroup as that which corresponds to the murine V region, has no rare framework residues, and the CDRs belong to the same Chothia canonical structure groups. No backmutations were made in Version 1 of humanized 12A11.
- the amino acid alignment of the reshaped heavy chain V region is shown in FIG. 9B .
- the choice for the acceptor framework (AAA69734 (SEQ ID NO: 11)) is from human subgroup III (as described previously) and has no rare framework residues.
- Structural analysis of the murine VH chain (1ETZ and 1JRH) in conjunction with the amino acid alignment of AAA69734 (SEQ ID NO: 11) to the murine sequence dictates 9 backmutations in version 1 (v1) of the reshaped heavy chain: A24F T28S F29L V37I V48L F67L R71K N73T L78V (Kabat numbering).
- the back mutations are highlighted by asterisks in the amino-acid alignment shown in FIG. 9B .
- residues are canonical residues (A24F, F29L, & R71K, solid fill), i.e. framework residues which may contribute to antigen binding by virtue of proximity to CDR residues.
- interface residues involved in VH-VL packing interactions underlined
- the N73T mutation is at a vernier residue (dotted fill) on the edge of the binding site, possibly interacting with S30 adjacent to CDR1.
- the remaining 4 residues targeted for back mutation (T28S, V48L, F67L, L78V, Kabat numbering) also fall into the vernier class (indirect contribution to CDR conformation, dotted fill in FIG. 9B ).
- Tables 11 and 12 set forth Kabat numbering keys for the various light and chains, respectively.
- Table 11 Key to Kabat Numbering for 12A11 Light Chain.
- Table 11 discloses residues 1-112 of SEQ ID NO:2, SEQ ID NO:7, residues 1-112 of SEQ ID NO: 8 and residues 1-100 of SEQ ID NO:9, respectively, in order of appearance.
- Table 12 discloses residues 1-120 of SEQ ID NO:4, SEQ ID NO:10, residues 1-122 of SEQ ID NO:11 and residues 1-118 of SEQ ID NO:12, respectively, in order of appearance.
- the humanized antibodies preferably exhibit a specific binding affinity for A ⁇ of at least 10 7 , 10 8 , 10 9 or 10 10 M ⁇ 1 .
- the upper limit of binding affinity of the humanized antibodies for A ⁇ is within a factor of three, four or five of that of 12A11 (i.e., ⁇ 10 9 M ⁇ ).
- the lower limit of binding affinity is also within a factor of three, four and five of that of 12A11.
- PCR-mediated assembly was used to generate h12A11v1 using appropriate oligonucleotide primers.
- the nucleotide sequences of humanized 12A11VL (version 1) (SEQ ID NO:34) and 12A11VH (version 1) (SEQ ID NO: 35) are listed below in Tables 13 and 14, respectively.
- the vernier residues contribute indirectly to CDR conformation and were postulated to be of least significance for conformational perturbation.
- the targeted residues were mutated by site-directed mutagenesis using a kit by Strategene and h12A11VHv1 in a pCRS plasmid as the mutagenesis template to arise at clones corresponding to version 2.
- a sequenced verified V-region insert of version 2 was subcloned into the BamHI/HindIII sites of the heavy chain expression vector pCMV-Cgamma1 (SEQ ID NOs: 57 and 58) to produce recombinant h12A11v2 antibody.
- a version 2.1 antibody was similarly created having each of the above vernier residue mutations (i.e., elimination of backmutations) in addition to mutation at position T73N.
- a version 3 antibody likewise had each of the above mutations, T28S, L48V, L67F, V78L, in addition to a mutation at position K71R.
- the amino acid sequences of humanized 12A11VH (version 2) (SEQ ID NO: 13), 12A11VH (version 2.1) (SEQ ID NO: 14), and 12A11VH (version 3) (SEQ ID NO: 15) are depicted in FIGS. 10A-C .
- Additional versions may include combinations of the above, for example, human residues at 1, 2, 3, 4 or 5 vernier residues in combination with at least one packing and/or canonical residue (e.g., human residues at positions 28, 37, 48, 67, 71 and 78 or human residues at positions 28, 37, 48, 67, 71, 73 and 78).
- a version 3.1 antibody was created having human residues at 1 vernier residue in combination with one packing residue and two canonical residues (i.e., human residues at positions 28, 48, 67, 71, 73 and 78).
- version 3.1 As compared to version 1 which has 21% mouse variable region residues (VL+VH), version 3.1 has only 17% mouse variable region residues (i.e., has a lower murine content).
- the amino acid sequences of humanized 12A11VH (version 3.1) (SEQ ID NO: 36) and humanized 12A11VH versions 4-6 (SEQ ID NOs: 16-29) are depicted in FIGS. 10A-C .
- a seventh version of humanized 12A11 is created having each of the backmutations indicated for version 1, except for the T ⁇ S backmutation at residue 28 (vernier), and the V ⁇ I backmutation at residue 37 (packing).
- An eighth version of humanized 12A11 is created having each of the backmutations indicated for version 1, except for the N ⁇ T backmutation at residue 73 (vernier).
- the amino acid sequences of humanized 12A11VH (version 7) (SEQ ID NO: 30) and humanized 12A11VH (version 8) (SEQ ID NOs: 16-31) are depicted in FIGS. 10A-C .
- version 7 contains only 7 backmutations.
- the T28S backmutation is conservative and is eliminated in version 7 of the heavy chain.
- the backmutation at packing residue V37I is also eliminated in version 7.
- version 7 contains only 8 backmutations.
- the N73T (vernier) backmutation is eliminated.
- Additional versions may include combinations of the above, for example, human residues (e.g., elimination of backmutations) at 1, 2, 3, 4 (or 5) residues selected from positions 28, 48, 78 and 73, optionally in combination with elimination of backmutation at least one packing residue (e.g., position 37) and/or at least one canonical residue.
- Humanized 12A11 versions were cloned in a pSMED2/pSMEN2 expression system.
- the coding sequence for each antibody was operably linked to a germline leader sequence to facilitate extracellular secretion.
- Humanized 12A11 was transiently expressed in COS cells for production of analytical quantities of antibody used in the functional testing described infra.
- CHO and HEK293 cell lines were subsequently transfected and transferred to suspension culture to provide stable expression of production levels of antibody for use in vivo.
- h12A11v3.1 in transiently-transfected COS cells was increased by manipulation of heavy chain introns.
- expression of h12A11v3.1 in a stably transfected pool was increased by manipulation of heavy chain intron content (i.e., deletion of introns between CH1 and hinge region, intron between the hinge region and CH2, and intron between CH2 and CH3) and signal sequence (i.e., use of the generic signal sequence MGWSCIILFLVATGAHS (SEQ ID NO:56). All humanized antibodies were purified according to art-recognized methodologies.
- Humanized 12A11 version 1 was further compared to its murine and chimeric counterparts for two properties: antigen binding (quantitative A ⁇ ELISA) and relative affinity.
- the binding activity of h12A11v1 was demonstrated in the quantitative A ⁇ ELISA and found to be identical with murine and chimeric forms of 12A11 (see FIG. 11 ).
- the affinity of h12A11v1 antibody was also compared with murine and chimeric 12A11 antibodies by a competitive A ⁇ ELISA.
- a biotin conjugated recombinant mouse 12A11C ⁇ 2a (isotype switched 12A11) was used.
- the binding activity of the biotinylated m12A11C ⁇ 2a for aggregate A ⁇ 1-42 was confirmed by an ELISA assay using streptavidin-HRP as reporter.
- FIG. 12 shows the result of h12A11v1 competitive assay comparing h12A11v1 with chimeric and murine forms.
- the humanized 12A11v1 competed within 2 ⁇ IC50 value with its murine and chimeric counterparts.
- This data is consistent with affinity determination using Biacore technology (data not shown), which indicated KD values of 38 nM and 23 nM for the murine C ⁇ 2a and h12A11v1, respectively.
- the findings suggest h12A11v1 retains the antigen binding properties and affinity of its original murine counterpart.
- COS cells were transiently transfected with different combinations of humanized 12A11VH and h12A11VLv1.
- the conditioned media was collected 72 hours post-transfection.
- Antibody concentration in conditioned media from transfected COS cells was determined by a quantitative human IgG ELISA.
- Quantitative A ⁇ (1-42) aggregate binding assay confirmed that h12A11 v2, v2.1 and v3 are comparable to h12A11v1 and to chimeric 12A11 for antigen binding.
- versions 5.1-5.6 and 6.1-6.3 exhibit similar binding activities when tested in this binding assay.
- Version 6.4 showed some loss of activity in the assay but activity was notably restored in v2.
- Binding properties for murine 12A11 and h12A11v1 were also compared using BIAcore technology.
- Murine 12A11 and h12A11v1 exhibited similar binding profiles when exposed to either low- or high-density immobilized A ⁇ peptide (bio-DAE peptide).
- Kinetic analysis of murine 12A11 versus h12A11v1 was also performed.
- the BIAcore technology was used to measure the binding of soluble antibody to solid phase bound biotinylated DAE peptide. The peptide was immobilized on streptavidin biosensor chips then, varying concentrations of each antibody were applied in triplicates and the binding was measured as a function of time.
- the kinetic data was analyzed using BIAevaluation software applied to a bivalent model.
- the apparent dissociation (k d ) and association (k a ) rate constants were calculated from the appropriate regions of the sensorgrams using a global analysis.
- the affinity constant of the interaction between bio-DAE10 and the antibodies was calculated from the kinetic rate constants. From these measurements the apparent dissociation (kd) and association (ka) rate constants were derived and used to calculate a K D value for the interaction.
- Table 15 includes a summary of kinetic analysis of A ⁇ binding of 12A11 antibodies as determined by BIAcore analysis.
- Table 16 includes a summary of kinetic analysis of A ⁇ binding of the various humanized 12A11 antibodies (as determined by BIAcore analysis).
- humanized 12A11 v1 and humanized 12A11 v3.1 have similar affinities for A ⁇ peptide when compare with parental murine 12A11 (h12A11v1>m12A11>chi12A11>h12A11v3.1>h12A11v2.1>h12A11v2>h12A11 v3.1).
- the affinity of humanized 12A11 v1 and humanized 12A11 v3.1 are within 2-3 ⁇ that of the chimeric 12A11 antibody as determined by competitive binding and/or BIAcore analysis.
- Humanized 12A11 v1 and humanized 12A11v3 were further tested for the ability to bind plaque and to clear plaques in an ex vivo assay. Immunohistochemistry was performed on cryostat sections from PDAPP and human AD brains. Humanized 12A11v1 and humanized 12A11v3 were compared to chimeric 12A11 and found to stain plaque in both PDAPP and human cryostat sections at all concentrations tested (i.e., 0.3 ⁇ g/ml, 1 ⁇ g/ml and 3 ⁇ g/ml).
- humanized 12A11v1 and humanized 12A11v3 were also tested in an ex vivo phagocytosis assay with primary mouse microglial cells and sections of brain tissue from PDAPP mice for their ability to clear plaque. Irrelevant IgG 1 antibody, having no reactivity toward A ⁇ or other components of the assay, was used as a negative control.
- Each of the humanized 12A11 v1, humanized 12A11v3 and chimeric 12A11 antibodies efficiently reduced A ⁇ levels when tested at a concentration of 0.3 ⁇ g/ml (data not shown).
- rNET replacement NET
- a profile was generated reflecting the effect of substitution with the various non-native residues at that position on binding activity (determined by capture ELISA). Profiles were likewise generated at successive positions (8 residues in total) along the antigenic peptide. The combined profile, or epitope map, (reflecting substitution at each position with all 19 non-native residues) was then be compared to maps similarly generated chimeric 12A11, humanized 12A11 v1 and humanized 12A11 v3.1. Notably, the specificity of humanized 12A11 v1 and humanized 12A11 v3.1 were the same or similar to the parent murine 12A11 antibody.
- each mouse was administered a CFC training session immediately following treatment and a CFC testing session within 24 hours of treatment (i.e. Day 1 post-treatment).
- the results of CFC assay are depicted in FIG. 14 .
- the data clearly indicate that mu12A11, chi12A11 and v3.1 hu 12A11 have a similar potency in rapidly improving cognition.
- a 3 mg/kg dose or greater of either chi 12A11 or v3.1 hu12A11 resulted in a memory deficit reversal that was similar in magnitude to the results obtained with a 1 mg/kg dose of mu12A11.
- Humanized 12A11 antibodies v1.0 through v3.1 also proved efficacious in the CFC assays, in particular, v1.0, v3.0 and v3.1, with v1.0 and v3.1 having efficacy similar to that of murine 12A11, and v3.0 further exhibiting significant efficacy.
- the mouse antibody 266 non-plaque binding
- was included as a positive control (MED 3 mg/kg).
- the invention provides for a number of uses.
- the invention provides for the use of any of the antibodies to A ⁇ described above in the treatment, prophylaxis or diagnosis of an A ⁇ related disease or disorder or an amyloidogenic disease or disorder, or in the manufacture of a medicament or diagnostic composition for use in the same.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/303,478 US8916165B2 (en) | 2004-12-15 | 2005-12-15 | Humanized Aβ antibodies for use in improving cognition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63677604P | 2004-12-15 | 2004-12-15 | |
US11/303,478 US8916165B2 (en) | 2004-12-15 | 2005-12-15 | Humanized Aβ antibodies for use in improving cognition |
Publications (2)
Publication Number | Publication Date |
---|---|
US20060198851A1 US20060198851A1 (en) | 2006-09-07 |
US8916165B2 true US8916165B2 (en) | 2014-12-23 |
Family
ID=36129797
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/303,478 Expired - Fee Related US8916165B2 (en) | 2004-12-15 | 2005-12-15 | Humanized Aβ antibodies for use in improving cognition |
Country Status (11)
Country | Link |
---|---|
US (1) | US8916165B2 (fr) |
EP (1) | EP1838348B1 (fr) |
JP (2) | JP2008523815A (fr) |
AR (1) | AR052051A1 (fr) |
CA (1) | CA2590337C (fr) |
ES (1) | ES2434732T3 (fr) |
HK (1) | HK1109585A1 (fr) |
PE (1) | PE20061329A1 (fr) |
TW (1) | TW200635607A (fr) |
UY (1) | UY29284A1 (fr) |
WO (1) | WO2006066089A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160120941A1 (en) * | 2013-05-31 | 2016-05-05 | Regeneron Pharmaceuticals, Inc. | Methods of using il-1 antagonists to treat alzheimer's disease |
US20180319856A1 (en) * | 2015-11-09 | 2018-11-08 | The University Of British Columbia | Epitopes in amyloid beta mid-region and conformationally-selective antibodies thereto |
US10751382B2 (en) | 2016-11-09 | 2020-08-25 | The University Of British Columbia | Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide |
US10759837B2 (en) * | 2015-11-09 | 2020-09-01 | The University Of British Columbia | Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide |
US10772969B2 (en) | 2015-11-09 | 2020-09-15 | The University Of British Columbia | N-terminal epitopes in amyloid beta and conformationally-selective antibodies thereto |
WO2022192636A1 (fr) | 2021-03-12 | 2022-09-15 | Eli Lilly And Company | Anticorps anti-amyloïde bêta et leurs utilisations |
WO2022251048A1 (fr) | 2021-05-24 | 2022-12-01 | Eli Lilly And Company | Anticorps anti-amyloïde bêta et leurs utilisations |
Families Citing this family (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7790856B2 (en) | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US7700751B2 (en) | 2000-12-06 | 2010-04-20 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize β-amyloid peptide |
MY139983A (en) | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
DE10303974A1 (de) | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
US20060188512A1 (en) * | 2003-02-01 | 2006-08-24 | Ted Yednock | Active immunization to generate antibodies to solble a-beta |
US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
TWI374893B (en) | 2003-05-30 | 2012-10-21 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
CA2544865C (fr) | 2003-11-05 | 2019-07-09 | Glycart Biotechnology Ag | Molecules fixatrices d'antigenes presentant une affinite de fixation du recepteur de fc et une fonction effectrice accrues |
CA2582194A1 (fr) * | 2004-10-05 | 2006-04-20 | Neuralab Limited | Procedes et compositions permettant d'ameliorer la fabrication de proteines recombinantes |
PE20061329A1 (es) | 2004-12-15 | 2006-12-08 | Neuralab Ltd | Anticuerpos ab humanizados para mejorar la cognicion |
EP1841455A1 (fr) * | 2005-01-24 | 2007-10-10 | Amgen Inc. | Anticorps anti-amyloide humanise |
GT200600031A (es) * | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
RU2415865C2 (ru) * | 2005-06-17 | 2011-04-10 | Вайет | СПОСОБЫ ОЧИСТКИ БЕЛКОВ, СОДЕРЖАЩИХ ОБЛАСТЬ Fc |
RU2482132C2 (ru) * | 2005-08-26 | 2013-05-20 | Роше Гликарт Аг | Модифицированные антигенсвязывающие молекулы с измененной клеточной сигнальной активностью |
AU2012216702B2 (en) * | 2005-08-26 | 2014-12-04 | Roche Glycart Ag | Modified antigen binding molecules with altered cell signaling activity |
RU2442793C2 (ru) | 2005-11-30 | 2012-02-20 | Эбботт Лэборетриз | АНТИТЕЛА ПРОТИВ ГЛОБУЛОМЕРА Аβ, ИХ АНТИГЕНСВЯЗЫВАЮЩИЕ ЧАСТИ, СООТВЕТСТВУЮЩИЕ ГИБРИДОМЫ, НУКЛЕИНОВЫЕ КИСЛОТЫ, ВЕКТОРЫ, КЛЕТКИ-ХОЗЯЕВА, СПОСОБЫ ПОЛУЧЕНИЯ УКАЗАННЫХ АНТИТЕЛ, КОМПОЗИЦИИ, СОДЕРЖАЩИЕ УКАЗАННЫЕ АНТИТЕЛА, ПРИМЕНЕНИЯ УКАЗАННЫХ АНТИТЕЛ И СПОСОБЫ ИСПОЛЬЗОВАНИЯ УКАЗАННЫХ АНТИТЕЛ |
KR20180058863A (ko) | 2005-11-30 | 2018-06-01 | 애브비 인코포레이티드 | 아밀로이드 베타 단백질에 대한 모노클로날 항체 및 이의 용도 |
EP2808032B1 (fr) | 2005-12-12 | 2018-08-01 | AC Immune S.A. | Anticorps specifiques pour a beta possédant des propriétés thérapeutiques |
US8784810B2 (en) | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
CL2007002070A1 (es) | 2006-07-14 | 2008-02-08 | Ac Immune S A Genentech Inc | Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade |
US8455626B2 (en) | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
WO2008104386A2 (fr) | 2007-02-27 | 2008-09-04 | Abbott Gmbh & Co. Kg | Méthode de traitement d'amyloïdoses |
CN101668525A (zh) | 2007-03-01 | 2010-03-10 | 前体生物药物股份公司 | 谷氨酰胺酰环化酶抑制剂的新用途 |
US8003097B2 (en) | 2007-04-18 | 2011-08-23 | Janssen Alzheimer Immunotherapy | Treatment of cerebral amyloid angiopathy |
EP2865670B1 (fr) | 2007-04-18 | 2017-01-11 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
US8613923B2 (en) | 2007-06-12 | 2013-12-24 | Ac Immune S.A. | Monoclonal antibody |
US8048420B2 (en) | 2007-06-12 | 2011-11-01 | Ac Immune S.A. | Monoclonal antibody |
SI2182983T1 (sl) | 2007-07-27 | 2014-09-30 | Janssen Alzheimer Immunotherapy | Zdravljenje amiloidogenih bolezni s humaniziranimi protitelesi proti abeta |
ES2473623T3 (es) * | 2007-08-20 | 2014-07-07 | Glaxo Group Limited | Procedimiento de producción |
AU2008311367B2 (en) | 2007-10-05 | 2014-11-13 | Ac Immune S.A. | Use of anti-amyloid beta antibody in ocular diseases |
AU2013209361B2 (en) * | 2007-10-17 | 2016-09-15 | Janssen Sciences Ireland Uc | Immunotherapy regimes dependent on ApoE status |
JO3076B1 (ar) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | نظم العلاج المناعي المعتمد على حالة apoe |
CA2709354C (fr) | 2007-12-21 | 2014-06-17 | Amgen Inc. | Anticorps anti-amyloide et utilisations de ceux-ci |
US8524863B2 (en) | 2008-10-06 | 2013-09-03 | Commonwealth Scientific And Industrial Research Organisation | Amyloid-beta peptide crystal structure |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
EP2475428B1 (fr) | 2009-09-11 | 2015-07-01 | Probiodrug AG | Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase |
WO2017120461A1 (fr) | 2016-01-08 | 2017-07-13 | The Board Of Trustees Of The Leland Stanford Junior University | Modulation du ccr3 pour le traitement de déficiences associées au vieillissement, et compositions utilisées pour cette modulation |
US10487148B2 (en) | 2010-01-28 | 2019-11-26 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for treating aging-associated impairments |
US20160208011A1 (en) | 2010-01-28 | 2016-07-21 | The Board Of Trustees Of The Leland Stanford Junior University | Ccr3 modulation in the treatment of aging-associated impairments, and compositions for practicing the same |
US9181233B2 (en) | 2010-03-03 | 2015-11-10 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
JP5826194B2 (ja) | 2010-03-03 | 2015-12-02 | アブリンクス ナームローゼ フェンノートシャップ | 二パラトープ性a−ベータ結合ポリペプチド |
AU2011226074B2 (en) | 2010-03-10 | 2015-01-22 | Vivoryon Therapeutics N.V. | Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) |
ES2684475T3 (es) | 2010-04-15 | 2018-10-03 | Abbvie Inc. | Proteínas que se unen a beta amiloide |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2012016173A2 (fr) | 2010-07-30 | 2012-02-02 | Ac Immune S.A. | Anticorps humanisés sûrs et fonctionnels |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
DK2686313T3 (en) | 2011-03-16 | 2016-05-02 | Probiodrug Ag | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
US9161968B2 (en) | 2011-04-08 | 2015-10-20 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of neuroprotection involving macrophage colony stimulating factor receptor agonists |
MA38632B1 (fr) | 2013-05-20 | 2019-10-31 | Genentech Inc | Anticorps anti-récepteur de transferrine et procédés d'utilisation |
US10905779B2 (en) | 2013-12-09 | 2021-02-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for screening human blood products comprising plasma using immunocompromised rodent models |
NZ720949A (en) * | 2013-12-09 | 2019-03-29 | Univ Leland Stanford Junior | Methods and compositions for treating aging-associated conditions |
EP3221362B1 (fr) | 2014-11-19 | 2019-07-24 | F.Hoffmann-La Roche Ag | Anticorps anti-récepteur de transferrine et procédés d'utilisation |
CN107250158B (zh) | 2014-11-19 | 2022-03-25 | 基因泰克公司 | 抗转铁蛋白受体/抗bace1多特异性抗体和使用方法 |
RU2017120039A (ru) | 2014-12-10 | 2019-01-10 | Дженентек, Инк. | Антитела к рецепторам гематоэнцефалического барьера и способы их применения |
CN107921085B (zh) | 2015-06-15 | 2021-10-22 | 小利兰·斯坦福大学托管委员会 | 用于治疗衰老相关病症的方法和组合物 |
EP4353320A3 (fr) | 2016-04-28 | 2024-05-15 | Alkahest, Inc. | Utilisation de plasma sanguin et fractions de plasma sanguin en tant que therapie pour lutter contre la croissance et la progression tumorale |
US10525107B2 (en) | 2016-08-18 | 2020-01-07 | Alkahest, Inc. | Blood plasma fractions as a treatment for aging-associated cognitive disorders |
US11040068B2 (en) | 2017-04-26 | 2021-06-22 | Alkahest, Inc. | Dosing regimen for treatment of cognitive and motor impairments with blood plasma and blood plasma products |
IL305904A (en) | 2017-04-26 | 2023-11-01 | Alkahest Inc | Dosage regimen for the treatment of cognitive and motor impairments using blood plasma and blood plasma products |
JP7330164B2 (ja) | 2017-07-18 | 2023-08-21 | ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア | アミロイドベータに対する抗体 |
DK3461819T3 (da) | 2017-09-29 | 2020-08-10 | Probiodrug Ag | Inhibitorer af glutaminylcyklase |
EP3728567B1 (fr) * | 2017-12-19 | 2023-07-05 | Chase Therapeutics Corporation | Méthode d'évaluation d'une synucléinopathie |
CN113226283A (zh) | 2018-10-04 | 2021-08-06 | 罗切斯特大学 | 通过操纵血浆重量摩尔渗透压浓度改善淋巴递送 |
BR112021006743A2 (pt) | 2018-10-26 | 2021-07-13 | Alkahest, Inc. | uso de plasma e frações plasmáticas para melhoria de dor, cicatrização de ferida e recuperação pós-operatória |
WO2020132230A2 (fr) | 2018-12-20 | 2020-06-25 | Genentech, Inc. | Fc d'anticorps modifiés et méthodes d'utilisation |
WO2021007439A1 (fr) * | 2019-07-09 | 2021-01-14 | Tavotek Biotherapeutics (Hong Kong) Limited | Anticorps bispécifiques se liant au tnf-alpha et à il-1bêta et utilisations associées |
Citations (384)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987002671A1 (fr) | 1985-11-01 | 1987-05-07 | International Genetic Engineering, Inc. | Assemblage modulaire de genes d'anticorps, anticorps ainsi prepares et utilisation |
US4666829A (en) | 1985-05-15 | 1987-05-19 | University Of California | Polypeptide marker for Alzheimer's disease and its use for diagnosis |
WO1987006838A1 (fr) | 1986-05-05 | 1987-11-19 | Praxis Biologics, Inc. | Conjugues immunogeniques |
JPS62267297A (ja) | 1986-05-15 | 1987-11-19 | Tokyo Met Gov Seishin Igaku Sogo Kenkyusho | 老人斑反応性モノクロ−ナル抗体、それを産生する細胞株及び該モノクロ−ナル抗体の製造方法 |
US4713366A (en) | 1985-12-04 | 1987-12-15 | The Ohio State University Research Foundation | Antigenic modification of polypeptides |
WO1988007089A1 (fr) | 1987-03-18 | 1988-09-22 | Medical Research Council | Anticorps alteres |
EP0285159A1 (fr) | 1987-03-31 | 1988-10-05 | Suntory Limited | Anticorps monoclonal contre une protéine humaine apparentée à l'amyloide |
WO1988010120A1 (fr) | 1987-06-24 | 1988-12-29 | Brigham And Women's Hospital | Traitement de maladies auto-immunitaires par administration orale d'auto-antigenes |
WO1989001343A1 (fr) | 1987-08-17 | 1989-02-23 | The Regents Of The University Of California | Anticorps cationises administres a travers la barriere sang-cerveau |
US4816397A (en) | 1983-03-25 | 1989-03-28 | Celltech, Limited | Multichain polypeptides or proteins and processes for their production |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
WO1989003687A1 (fr) | 1987-10-23 | 1989-05-05 | Genetics Institute, Inc. | Composition et procede de traitement des cancers caracterises par la surexpression du proto-oncogene c-fms |
WO1989006242A1 (fr) | 1987-10-08 | 1989-07-13 | The Mclean Hospital Corporation | Anticorps agissant sur un peptide de l'amyloide de sequence a4 |
WO1989006689A1 (fr) | 1988-01-13 | 1989-07-27 | The Mclean Hospital Corporation | Constructions genetiques renfermant le gene amyloide cerebral d'alzheimer |
US4879213A (en) | 1986-12-05 | 1989-11-07 | Scripps Clinic And Research Foundation | Synthetic polypeptides and antibodies related to Epstein-Barr virus early antigen-diffuse |
US4883666A (en) | 1987-04-29 | 1989-11-28 | Massachusetts Institute Of Technology | Controlled drug delivery system for treatment of neural disorders |
GB2220211A (en) | 1988-06-29 | 1990-01-04 | Ribi Immunochem Research Inc | Modified lipopolysaccharides |
US4912206A (en) | 1987-02-26 | 1990-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | CDNA clone encoding brain amyloid of alzheimer's disease |
WO1990005142A1 (fr) | 1988-11-10 | 1990-05-17 | Imperial Cancer Research Technology Ltd. | Polypeptides |
WO1990007861A1 (fr) | 1988-12-28 | 1990-07-26 | Protein Design Labs, Inc. | IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2 |
EP0391714A2 (fr) | 1989-04-05 | 1990-10-10 | BRIGHAM & WOMEN'S HOSPITAL | Procédé pour la détection de la maladie d'Alzheimer: examen du tissu non-nerval |
US4966753A (en) | 1987-08-18 | 1990-10-30 | Molecular Rx, Inc. | Immunotherapeutic methods and compositions employing antigens characteristic of malignant neoplasms |
WO1990012871A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal sv17-6e10 specifique de la proteine amyloide cerebrovasculaire |
WO1990012870A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal du peptide amyloide |
WO1990014837A1 (fr) | 1989-05-25 | 1990-12-13 | Chiron Corporation | Composition d'adjuvant comprenant une emulsion de gouttelettes d'huile d'une taille inferieure au micron |
WO1990014840A1 (fr) | 1989-06-06 | 1990-12-13 | California Biotechnology Inc. | Proteine d'amyloide d'alzheimer recombinante |
WO1991008760A1 (fr) | 1989-12-20 | 1991-06-27 | Brigham And Women's Hospital | Traitement ameliore de maladies auto-immunes par administration par aerosol d'auto-antigenes |
WO1991009967A1 (fr) | 1989-12-21 | 1991-07-11 | Celltech Limited | Anticorps humanises |
WO1991010741A1 (fr) | 1990-01-12 | 1991-07-25 | Cell Genesys, Inc. | Generation d'anticorps xenogeniques |
WO1991012816A1 (fr) | 1990-03-02 | 1991-09-05 | Autoimmune, Inc. | Amelioration de la regulation reductrice de maladies autoimmunes par administration orale d'autoantigenes |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
EP0451700A1 (fr) | 1990-04-10 | 1991-10-16 | Miles Inc. | Minigènes APP recombinants pour l'expression dans des souris transgéniques comme modèles de la maladie d'Alzheimer |
WO1991016928A1 (fr) | 1990-04-27 | 1991-11-14 | Celltech Limited | ANTICORPS ANTI-MOLECULE 1 d'ADHERENCE INTERCELLULAIRE CHIMERIQUE ADAPTES AU MODELE HUMAIN, PROCEDE DE PREPARATION ET D'UTILISATION |
WO1991016819A1 (fr) | 1990-04-27 | 1991-11-14 | Molecular Rx., Inc. | Procede et composition servant a traiter des etats pathologiques du systeme nerveux central associes a la proteine beta amyloide anormale |
WO1991017271A1 (fr) | 1990-05-01 | 1991-11-14 | Affymax Technologies N.V. | Procedes de triage de banques d'adn recombine |
WO1991019810A1 (fr) | 1990-06-15 | 1991-12-26 | California Biotechnology Inc. | Mammifere transgenique non humain presentant la pathologie de formation d'amyloides de la maladie d'alzheimer |
WO1991019795A1 (fr) | 1990-06-19 | 1991-12-26 | Immuvax | Variantes de virus non pathognes |
WO1992001047A1 (fr) | 1990-07-10 | 1992-01-23 | Cambridge Antibody Technology Limited | Procede de production de chainon de paires a liaison specifique |
WO1992001059A1 (fr) | 1990-07-05 | 1992-01-23 | Celltech Limited | Anticorps diriges contre l'antigene carcino-embryonnaire (cea) et a greffe de zones determinant la complementarite (cdr) et production de ces anticorps |
US5096706A (en) | 1986-03-25 | 1992-03-17 | National Research Development Corporation | Antigen-based treatment for adiposity |
WO1992005793A1 (fr) | 1990-10-05 | 1992-04-16 | Medarex, Inc. | Immunostimulation ciblee induite par des reactifs bispecifiques |
WO1992006187A1 (fr) | 1990-09-28 | 1992-04-16 | The Upjohn Company | Animaux transgeniques porteurs d'un gene de precurseur amyloide d'alzheimer |
WO1992006708A1 (fr) | 1990-10-15 | 1992-04-30 | Brigham And Women's Hospital | Traitement de maladies auto-immunes par administration orale d'auto-antigenes |
WO1992007944A1 (fr) | 1990-10-26 | 1992-05-14 | Lynxvale Limited | Vecteur de la vaccine, genes de la vaccine et leurs produits d'expression |
WO1992013069A1 (fr) | 1991-01-21 | 1992-08-06 | Imperial College Of Science, Technology & Medicine | Test et modele pour la maladie d'alzheimer |
WO1992015330A1 (fr) | 1991-03-01 | 1992-09-17 | Rhône Merieux | Procede d'immunoneutralisation anti-lhrh des animaux domestiques males non castres et peptide pour cela |
WO1992019267A1 (fr) | 1991-05-08 | 1992-11-12 | Schweiz. Serum- & Impfinstitut Bern | Virosomes de la grippe reconstitues immunostimulants et immunopotentialisants et vaccins en contenant |
WO1992022653A1 (fr) | 1991-06-14 | 1992-12-23 | Genentech, Inc. | Procede de production d'anticorps humanises |
WO1993002189A1 (fr) | 1991-07-18 | 1993-02-04 | The Regents Of The University Of California | Modeles animaux transgeniques pour l'etude de la maladie d'alzheimer |
US5187153A (en) | 1986-11-17 | 1993-02-16 | Scios Nova Inc. | Methods of treatment using Alzheimer's amyloid polypeptide derivatives |
WO1993004194A1 (fr) | 1991-08-13 | 1993-03-04 | Regents Of The University Of Minnesota | Peptide meta-amyloide marque et depistage de la maladie d'alzheimer |
US5192753A (en) | 1991-04-23 | 1993-03-09 | Mcgeer Patrick L | Anti-rheumatoid arthritic drugs in the treatment of dementia |
US5208036A (en) | 1985-01-07 | 1993-05-04 | Syntex (U.S.A.) Inc. | N-(ω, (ω-1)-dialkyloxy)- and N-(ω, (ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US5220013A (en) | 1986-11-17 | 1993-06-15 | Scios Nova Inc. | DNA sequence useful for the detection of Alzheimer's disease |
WO1993012227A1 (fr) | 1991-12-17 | 1993-06-24 | Genpharm International, Inc. | Animaux transgeniques non humains capables de produire des anticorps heterologues |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5227159A (en) | 1989-01-31 | 1993-07-13 | Miller Richard A | Anti-idiotype antibodies reactive with shared idiotopes expressed by B cell lymphomas and autoantibodies |
WO1993014200A1 (fr) | 1992-01-07 | 1993-07-22 | Tsi Corporation | Modeles d'animaux transgeniques utilises pour tester des traitements potentiels relatifs a la maladie d'alzheimer |
US5231000A (en) | 1987-10-08 | 1993-07-27 | The Mclean Hospital | Antibodies to A4 amyloid peptide |
US5231170A (en) | 1986-08-27 | 1993-07-27 | Paul Averback | Antibodies to dense microspheres |
WO1993015760A1 (fr) | 1992-02-11 | 1993-08-19 | U.S. Government, As Represented By The Secretary Of The Army | Structure immunogene a double vecteur |
WO1993016724A1 (fr) | 1992-02-28 | 1993-09-02 | Autoimmune, Inc. | Suppression de maladies auto-immunes par des antigenes en attente |
US5245015A (en) | 1991-04-26 | 1993-09-14 | Tanox Biosystems, Inc. | Monoclonal antibodies which neutralize HIV-1 through reaction with a conformational epitope in vitro |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
WO1993021950A1 (fr) | 1992-04-28 | 1993-11-11 | Medeva Holdings Bv | Compositions de vaccin a administration par la muqueuse |
EP0276723B1 (fr) | 1987-01-30 | 1993-12-08 | Bayer Ag | Précurseur protéinique de polypeptide-APC, ADN le codant et utilisation diagnostique de cet ADN et de cette protéine |
US5270165A (en) | 1990-04-24 | 1993-12-14 | The Reagents Of The University Of California | Method of diagnosis of amyloidoses |
WO1994000153A1 (fr) | 1992-06-25 | 1994-01-06 | Smithkline Beecham Biologicals (S.A.) | Composition vaccinale contenant des adjuvants |
US5278049A (en) | 1986-06-03 | 1994-01-11 | Incyte Pharmaceuticals, Inc. | Recombinant molecule encoding human protease nexin |
WO1994001772A1 (fr) | 1992-07-13 | 1994-01-20 | The Children's Medical Center Corporation | CRIBLAGE DE TRAITEMENTS DE LA MALADIE D'ALZHEIMER SUR LA BASE DE LA PRODUCTION DE β-AMYLOIDE |
WO1994003208A1 (fr) | 1992-07-30 | 1994-02-17 | Yeda Research And Development Company Ltd. | Conjugues d'antigenes faiblement immunogenes et porteurs de peptides synthetiques et vaccins les contenant |
WO1994003615A1 (fr) | 1992-07-31 | 1994-02-17 | Medeva Holdings B.V. | Expression de proteines recombinantes fusionnees dans des bacteries attenuees |
WO1994005311A1 (fr) | 1992-08-27 | 1994-03-17 | Deakin Research Limited | Analogues peptidiques de synthese a modifications retro, inverse ou retro-inverse |
WO1994009364A1 (fr) | 1992-10-13 | 1994-04-28 | Duke University | Procede permettant d'inhiber la liaison de la proteine precurseur d'amyloide a la proteine beta-amyloide |
WO1994009823A1 (fr) | 1992-11-03 | 1994-05-11 | Oravax, Inc. | Vaccin a base d'urease contre l'infection due a l'helicobacter |
WO1994010569A1 (fr) | 1992-10-26 | 1994-05-11 | Schenk Dale B | PROCEDES ET COMPOSITIONS VISANT A DETECTER UN PEPTIDE β-AMYLOIDE SOLUBLE |
EP0597101A1 (fr) | 1991-07-20 | 1994-05-18 | Hagiwara, Yoshihide | Preparation a anticorps monoclonal humain stabilise |
WO1994016731A1 (fr) | 1993-01-22 | 1994-08-04 | Sloan-Kettering Institute For Cancer Research | Vaccins de conjugue ganglioside-klh avec qs-21 |
WO1994017197A1 (fr) | 1993-01-25 | 1994-08-04 | Takeda Chemical Industries, Ltd. | ANTICORPS DIRIGE CONTRE LE β-AMYLOIDE OU UN DERIVE DE CE DERNIER ET SON UTILISATION |
EP0613007A2 (fr) | 1993-02-22 | 1994-08-31 | Eli Lilly And Company | Analyse pharmaceutique et anticorps |
EP0616814A1 (fr) | 1993-03-26 | 1994-09-28 | Bristol-Myers Squibb Company | Compositions à libération contrôlée de TGF-bêta biologiquement actif |
WO1994021288A1 (fr) | 1993-03-18 | 1994-09-29 | Cytimmune Sciences, Inc. | Composition et methode d'abaissement de la toxicite de facteurs biologiquement actifs |
US5358708A (en) | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
WO1994028412A1 (fr) | 1993-05-28 | 1994-12-08 | The Miriam Hospital | Composition et procede d'imagerie in vivo de depots d'amyloide |
WO1994029459A1 (fr) | 1993-06-04 | 1994-12-22 | Whitehead Institute For Biomedical Research | Proteines du stress et leurs utilisations |
US5385887A (en) | 1993-09-10 | 1995-01-31 | Genetics Institute, Inc. | Formulations for delivery of osteogenic proteins |
WO1995004151A2 (fr) | 1993-07-30 | 1995-02-09 | Medeva Holdings B.V. | Compositions vaccinales comprenant des proteines de fusion tetc de recombinaison |
WO1995005393A2 (fr) | 1993-08-18 | 1995-02-23 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Peptides liant et neturalisant les lipopolysaccharides |
WO1995005849A1 (fr) | 1993-08-26 | 1995-03-02 | Mouritsen & Elsner A/S | Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes |
WO1995005853A1 (fr) | 1993-08-26 | 1995-03-02 | The Regents Of The University Of California | Procede, compositions et dispositifs pour l'administration de polynucleotides nus qui codent des peptides a activite biologique |
WO1995006407A1 (fr) | 1993-08-30 | 1995-03-09 | The Regents Of The University Of California | Nouveau composant amyloide lie a la maladie d'alzheimer et procedes d'utilisation |
WO1995007301A1 (fr) | 1993-09-07 | 1995-03-16 | Smithkline Beecham Corporation | Anticorps recombines contre l'il4 utiles dans le traitement des affections induites par l'il4 |
WO1995007707A1 (fr) | 1993-09-14 | 1995-03-23 | Cytel Corporation | Alteration de la reponse immunitaire a l'aide de peptides se liant a des alleles pan dr |
WO1995008999A1 (fr) | 1993-09-29 | 1995-04-06 | City Of Hope | TRAITEMENT DE L'AMNESIE DUE AU DEPOT DE LA PROTEINE AMYLOIDE β DANS LA MALADIE D'ALZHEIMER |
WO1995011008A2 (fr) | 1993-10-22 | 1995-04-27 | Genentech, Inc. | Procedes et compositions de microencapsulation d'adjuvants |
WO1995011311A1 (fr) | 1993-10-20 | 1995-04-27 | Duke University | PROCEDE DE LIAISON D'UN ELEMENT AU PEPTIDE β-AMYLOÏDE |
WO1995011994A1 (fr) | 1993-10-27 | 1995-05-04 | Athena Neurosciences, Inc. | Procede de detection d'inhibiteurs de la production de peptides beta-amyloides |
WO1995012815A1 (fr) | 1993-11-04 | 1995-05-11 | The Research Foundation Of State University Of New York | PROCEDE EMPECHANT L'AGGLUTINATION DES PROTEINES β AMYLOIDES |
US5417986A (en) | 1984-03-16 | 1995-05-23 | The United States Of America As Represented By The Secretary Of The Army | Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres |
JPH07132033A (ja) | 1993-11-12 | 1995-05-23 | Hoechst Japan Ltd | アルツハイマー病モデルトランスジェニック動物 |
JPH07165799A (ja) | 1993-10-22 | 1995-06-27 | Tomoyasu Ra | 抗ヒト高親和性IgE受容体モノクローナル抗体に係るアミノ酸配列を有するポリペプチド、及びこれをコードするDNA断片 |
WO1995017085A1 (fr) | 1993-12-20 | 1995-06-29 | Genzyme Transgenics Corporation | Production transgenique d'anticorps dans le lait |
US5434170A (en) | 1993-12-23 | 1995-07-18 | Andrulis Pharmaceuticals Corp. | Method for treating neurocognitive disorders |
US5441870A (en) | 1992-04-15 | 1995-08-15 | Athena Neurosciences, Inc. | Methods for monitoring cellular processing of β-amyloid precursor protein |
WO1995023166A1 (fr) | 1994-02-25 | 1995-08-31 | Deakin Research Limited | Epitopes de lymphocytes t inverses ou retro-inverses synthetiques |
WO1995023860A2 (fr) | 1994-03-04 | 1995-09-08 | Genentech, Inc. | PROTEINES INHIBITRICES PROPRES AU DOMAINE DE KÜNITZ DERIVEES DE L'INHIBITEUR DU PRECURSEUR DE LA β-PROTEINE AMYLOIDE DE LA MALADIE D'ALZHEIMER |
US5464823A (en) | 1993-07-20 | 1995-11-07 | The Regents Of The University Of California | Mammalian antibiotic peptides |
WO1995031996A1 (fr) | 1994-05-25 | 1995-11-30 | Milkhaus Lab | Compositions et procedes de traitement de maladies a formation de plaque |
US5472693A (en) | 1993-02-16 | 1995-12-05 | The Dow Chemical Company | Family of anti-carcinoembryonic antigen chimeric antibodies |
WO1996001126A1 (fr) | 1994-07-06 | 1996-01-18 | Immunomedics, Inc. | Vaccin multietape stimulant les reactions immunitaires en cascade |
WO1996003144A1 (fr) | 1994-07-27 | 1996-02-08 | The Council Of The Queensland Institute Of Medical Research | Vaccins a base de polyepitopes |
WO1996008665A1 (fr) | 1994-09-12 | 1996-03-21 | Ina Wälzlager Schaeffler Kg | Element de transmission pour commande de changement de vitesses |
US5514548A (en) | 1993-02-17 | 1996-05-07 | Morphosys Gesellschaft Fur Proteinoptimerung Mbh | Method for in vivo selection of ligand-binding proteins |
WO1996014061A1 (fr) | 1994-11-03 | 1996-05-17 | Cell Genesys, Inc. | Nouveaux vecteurs adenoviraux, lignees cellulaires d'encapsidation, adenovirus recombines et procedes |
WO1996015799A1 (fr) | 1994-11-22 | 1996-05-30 | Rutgers, The State University Of New Jersey | Methodes de prevention ou de traitement des hemorragies vasculaires et de la maladie d'alzheimer |
WO1996018900A1 (fr) | 1994-12-16 | 1996-06-20 | Ramot-Univ. Authority For Applied Research And Industrial Development Ltd. | Prevention de l'agregation des proteines |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
WO1996025435A1 (fr) | 1995-02-14 | 1996-08-22 | Bayer Corporation | ANTICORPS MONOCLONAL SPECIFIQUE DU PEPTIDE βA4 |
WO1996028471A1 (fr) | 1995-03-14 | 1996-09-19 | Praecis Pharmaceuticals Incorporated | Modulateurs de l'agregation de substances amyloides |
WO1996029421A1 (fr) | 1995-03-23 | 1996-09-26 | Cantab Pharmaceuticals Research Limited | Vecteurs d'apport de genes |
WO1996022373A3 (fr) | 1995-01-17 | 1996-10-03 | Univ Kentucky | Anticorps monoclonal 1a7 et son utilisation pour le traitement des melanomes et des carcinomes des petites cellules |
WO1996033739A1 (fr) | 1995-04-25 | 1996-10-31 | Smithkline Beecham Biologicals S.A. | Vaccins contenant une saponine ainsi qu'un sterol |
US5571499A (en) | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
US5571500A (en) | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases through administration by inhalation of autoantigens |
US5576184A (en) | 1988-09-06 | 1996-11-19 | Xoma Corporation | Production of chimeric mouse-human antibodies with specificity to human tumor antigens |
WO1996037621A2 (fr) | 1995-05-23 | 1996-11-28 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Proteines multimeres |
US5583112A (en) | 1987-05-29 | 1996-12-10 | Cambridge Biotech Corporation | Saponin-antigen conjugates and the use thereof |
WO1996039176A1 (fr) | 1995-06-05 | 1996-12-12 | Brigham & Women's Hospital | Utilisation de la tolerance orale pour supprimer les reponses immunitaires de th1 et de th2 et pour supprimer la production d'anticorps |
WO1996039834A1 (fr) | 1995-06-07 | 1996-12-19 | New York University | Peptides et compositions pharmaceutiques a base de tels peptides, destinees au traitement de troubles ou d'affections associees a un pliage anormal de proteine dans des depots amyloides ou de type amyloide |
WO1996040895A1 (fr) | 1995-06-07 | 1996-12-19 | Athena Neurosciences, Inc. | Procede d'identification de therapies de la maladie d'alzheimer a l'aide de modeles animaux transgeniques |
US5593846A (en) | 1992-07-10 | 1997-01-14 | Athena Neurosciences | Methods for the detection of soluble β-amyloid peptide |
US5601827A (en) | 1992-06-18 | 1997-02-11 | President And Fellows Of Harvard College | Diphtheria toxin vaccines |
WO1997005164A1 (fr) | 1995-07-27 | 1997-02-13 | Csl Limited | Produits de recombinaison de polyproteine de papillomavirus |
US5605811A (en) | 1992-10-26 | 1997-02-25 | Athena Neurosciences, Inc. | Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein |
WO1997008320A1 (fr) | 1995-08-18 | 1997-03-06 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Banques de proteines/(poly)peptides |
WO1997010505A1 (fr) | 1995-09-14 | 1997-03-20 | The Regents Of The University Of California | ANTICORPS SPECIFIQUE DU PrPSc NATIF |
WO1997003192A3 (fr) | 1995-07-07 | 1997-04-03 | Darwin Molecular Corp | Gene du chromosome 1 et produits genetiques lies a la maladie d'alzheimer |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US5620844A (en) | 1984-03-07 | 1997-04-15 | New York Blood, Inc. | Assays for detecting hepatitis B virus envelope antigens or antibodies thereto and diagnostic test kits for use in performing the assays |
WO1997013855A1 (fr) | 1995-10-10 | 1997-04-17 | Novartis Ag | Proteine associee a un melanome |
US5622701A (en) | 1994-06-14 | 1997-04-22 | Protein Design Labs, Inc. | Cross-reacting monoclonal antibodies specific for E- and P-selectin |
US5624937A (en) | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
WO1997017613A1 (fr) | 1995-11-10 | 1997-05-15 | Elan Corporation, Plc | Peptides favorisant le transport dans les tissus et procedes d'identification et d'utilisation correspondants |
WO1997018855A1 (fr) | 1995-11-21 | 1997-05-29 | Eduard Naumovich Lerner | Dispositif pour ameliorer l'administration a l'organisme de substances et de composes biologiquement actifs |
WO1997021728A1 (fr) | 1995-12-12 | 1997-06-19 | Karolinska Innovations Ab | PEPTIDE FIXANT LA SEQUENCE KLVFF DE L'AMYLOIDE $g(b) |
US5641473A (en) | 1987-06-24 | 1997-06-24 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
US5641474A (en) | 1987-06-24 | 1997-06-24 | Autoimmune, Inc. | Prevention of autoimmune diseases by aerosol administration of autoantigens |
EP0783104A1 (fr) | 1995-12-27 | 1997-07-09 | Oriental Yeast Co., Ltd. | Procédé de dosage du précurseur de l'amyloide |
US5652334A (en) | 1993-09-08 | 1997-07-29 | City Of Hope | Method for design of substances that enhance memory and improve the quality of life |
WO1997026913A1 (fr) | 1996-01-26 | 1997-07-31 | The Trustees Of Columbia University In The City Of New York | POLYPEPTIDE PROVENANT D'UN EXTRAIT DE POUMON ET SE FIXANT A UN PEPTIDE AMYLOÏDE-$g(b) |
JPH09208485A (ja) | 1996-01-31 | 1997-08-12 | Teijin Ltd | ペプチド・蛋白質性薬物の水難溶性組成物 |
WO1997028816A1 (fr) | 1996-02-09 | 1997-08-14 | Ludwig Institute For Cancer Research | Compositions contenant des molecules immunogenes et facteur de stimulation de colonie de granulocytes-macrophages en tant qu'adjuvant |
WO1997032017A1 (fr) | 1996-02-26 | 1997-09-04 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Nouvelle methode pour l'identification de sequences d'acides nucleiques codant pour deux (poly)peptides interactifs, ou plus |
WO1997037031A1 (fr) | 1996-03-29 | 1997-10-09 | University Of Otago | Vecteurs de parapoxvirus |
WO1997036601A1 (fr) | 1996-04-03 | 1997-10-09 | Anergen, Inc. | Vaccins a peptides cycliques destines au traitement et a la prevention du diabete |
US5677425A (en) | 1987-09-04 | 1997-10-14 | Celltech Therapeutics Limited | Recombinant antibody |
US5679348A (en) | 1992-02-03 | 1997-10-21 | Cedars-Sinai Medical Center | Immunotherapy for recurrent HSV infections |
WO1997040147A1 (fr) | 1996-04-19 | 1997-10-30 | The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services | Regions reactives aux antigenes de la polyproteine du virus de l'hepatite a |
US5702906A (en) | 1990-09-25 | 1997-12-30 | Genentech, Inc. | Antibodies to neurotrophic factor-4 (NT-4) |
WO1998002462A1 (fr) | 1996-07-16 | 1998-01-22 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Domaines de la superfamille des immunoglobulines et fragments presentant une solubilite accrue |
WO1998004720A1 (fr) | 1996-07-26 | 1998-02-05 | Sloan-Kettering Institute For Cancer Research | Procedes et reactifs destines a l'immunisation genetique |
WO1998005350A1 (fr) | 1996-08-08 | 1998-02-12 | Milkhaus Laboratory, Inc. | Materiaux et procedes de traitement de maladies en plaques |
WO1998007850A2 (fr) | 1996-08-22 | 1998-02-26 | Bergmann Johanna E | Agents pour la detection pre-symptomatique et le ciblage therapeutique de la maladie d'alzheimer et du syndrome de down chez l'homme |
US5723130A (en) | 1993-05-25 | 1998-03-03 | Hancock; Gerald E. | Adjuvants for vaccines against respiratory syncytial virus |
WO1998008868A1 (fr) | 1996-08-27 | 1998-03-05 | Praecis Pharmaceuticals Incorporated | Modulateurs de l'agregation de peptides beta-amyloides, comprenant des d-aminoacides |
US5731284A (en) | 1995-09-28 | 1998-03-24 | Amgen Inc. | Method for treating Alzheimer's disease using glial line-derived neurotrophic factor (GDNF) protein product |
US5733547A (en) | 1987-06-24 | 1998-03-31 | Autoimmune, Inc. | Treatment of autoimmune arthritis by oral administration of type I or type III collagen |
US5733548A (en) | 1993-03-17 | 1998-03-31 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Immunogenic chimeras comprising nucleic acid sequences encoding endoplasmic reticulum signal sequence peptides and at least one other peptide, and their uses in vaccines and disease treatments |
US5744132A (en) | 1995-02-06 | 1998-04-28 | Genetics Institute, Inc. | Formulations for IL-12 |
WO1998008098A3 (fr) | 1996-08-22 | 1998-04-30 | Christian Fledelius | Detection d'acides amines-d dans les fluides corporels |
US5750361A (en) | 1995-11-02 | 1998-05-12 | The Regents Of The University Of California | Formation and use of prion protein (PRP) complexes |
WO1998022120A1 (fr) | 1996-11-19 | 1998-05-28 | The Wistar Institute Of Anatomy & Biology | Reactifs pour traiter et diagnostiquer la maladie d'alzheimer |
EP0845270A1 (fr) | 1996-03-23 | 1998-06-03 | The Research Foundation For Microbial Diseases Of Osaka University | Antigene a fragment fonctionnel de la toxine du tetanos, et vaccin contre le tetanos |
US5770700A (en) | 1996-01-25 | 1998-06-23 | Genetics Institute, Inc. | Liquid factor IX formulations |
US5773007A (en) | 1990-09-17 | 1998-06-30 | National Research Council Of Canada | Vaccine compositions |
US5776468A (en) | 1993-03-23 | 1998-07-07 | Smithkline Beecham Biologicals (S.A.) | Vaccine compositions containing 3-0 deacylated monophosphoryl lipid A |
US5780587A (en) | 1990-08-24 | 1998-07-14 | President And Fellows Of Harvard College | Compounds and methods for inhibiting β-protein filament formation and neurotoxicity |
WO1998033815A1 (fr) | 1997-02-05 | 1998-08-06 | Northwestern University | PROTEINE AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
US5798102A (en) | 1997-03-04 | 1998-08-25 | Milkhaus Laboratory, Inc. | Treatment of cardiomyopathy |
WO1998039303A1 (fr) | 1997-03-03 | 1998-09-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Petites molecules convenant au traitement d'une maladie inflammatoire |
US5817626A (en) | 1995-03-14 | 1998-10-06 | Praecis Pharmaceuticals Incorporated | Modulators of beta-amyloid peptide aggregation |
EP0868918A2 (fr) | 1993-12-23 | 1998-10-07 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | Vaccins |
WO1998044955A1 (fr) | 1997-04-09 | 1998-10-15 | Mindset Ltd. | Anticorps recombines specifiques contre les terminaisons beta-amyloide, codage par molecule d'adn, et leurs procedes d'utilisation |
US5824322A (en) | 1995-08-21 | 1998-10-20 | Cytrx Corporation | Compositions and methods for growth promotion |
WO1998046642A1 (fr) | 1997-04-15 | 1998-10-22 | Farmaceutisk Laboratorium Ferring A/S | MOLECULES TNFα MODIFIEES, ADN CODANT POUR CES MOLECULES ET VACCINS COMPRENANT CES MOLECULES TNFα MODIFIEES ET CET ADN |
US5837268A (en) | 1991-10-16 | 1998-11-17 | University Of Saskatchewan | GnRH-leukotoxin chimeras |
US5837672A (en) | 1992-07-10 | 1998-11-17 | Athena Neurosciences, Inc. | Methods and compositions for the detection of soluble β-amyloid peptide |
WO1998056418A1 (fr) | 1997-06-13 | 1998-12-17 | Genentech, Inc. | Formulation stabilisee renfermant un anticorps |
US5854215A (en) | 1995-03-14 | 1998-12-29 | Praecis Pharmaceuticals Incorporated | Modulators of β-amyloid peptide aggregation |
WO1999000150A2 (fr) | 1997-06-27 | 1999-01-07 | Regents Of The University Of California | Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline |
US5858981A (en) | 1993-09-30 | 1999-01-12 | University Of Pennsylvania | Method of inhibiting phagocytosis |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US5866129A (en) | 1989-06-21 | 1999-02-02 | Tanox Biosystems, Inc. | Method of producing an antibody with a peptide corresponding to membrane-bound IgA |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US5869054A (en) | 1987-06-24 | 1999-02-09 | Autoimmune Inc. | Treatment of multiple sclerosis by oral administration of autoantigens |
WO1999006587A2 (fr) | 1997-08-01 | 1999-02-11 | Morphosys Ag | Nouvelle methode et nouveau phage d'identification d'une sequence d'acide nucleique |
WO1999006545A2 (fr) | 1997-08-01 | 1999-02-11 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Composition et nouveau procede pour depister les maladies dues a la formation d'agregats de proteines ou de fibrilles du type amyloide |
WO1999006066A2 (fr) | 1997-07-30 | 1999-02-11 | Abiogen Pharma S.P.A. | Anticorps monoclonaux catalytiques a activite protease permettant la lyse selective de la fraction proteinique des plaques et agregats lies a certaines pathologies |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
WO1999010008A1 (fr) | 1997-08-29 | 1999-03-04 | Aquila Biopharmaceuticals, Inc. | Compositions renfermant l'adjuvant qs-21 et du polysorbate ou de la cyclodextrine comme excipient |
US5891991A (en) | 1992-04-20 | 1999-04-06 | The General Hospital Corporation | Amyloid precursor-like protein and uses thereof |
US5895654A (en) | 1996-01-25 | 1999-04-20 | Provost Fellows & Scholars Of The College Of The Univ. Of The Holy Undivided Trinity Of Queen Elisabeth | Streptococcus equi vaccine |
US5910427A (en) | 1995-06-22 | 1999-06-08 | La Jolla Institute For Allergy And Immunology | Antigen non-specific glycosylation inhibiting factor derivatives |
WO1999027944A1 (fr) | 1997-12-02 | 1999-06-10 | Neuralab Limited | Prevention et traitement de maladie amyloidogene |
WO1999027911A1 (fr) | 1997-12-03 | 1999-06-10 | Fujisawa Pharmaceutical Co., Ltd. | Medicament en pastilles souples et procede de fabrication |
WO1999027949A1 (fr) | 1997-12-03 | 1999-06-10 | Brigham And Women's Hospital | PROCEDES DE SUPPRESSION DES MODIFICATIONS LIEES AUX β-AMYLOIDES DANS LA MALADIE D'ALZHEIMER |
AU707083B2 (en) | 1993-08-26 | 1999-07-01 | Bavarian Nordic Inc. | Inducing antibody response against self-proteins with the aid of foreign T-cell epitopes |
EP0561087B1 (fr) | 1992-03-20 | 1999-08-04 | N.V. Innogenetics S.A. | Forme mutée du gène de la protéine du précurseur beta-amyloide |
US5935927A (en) | 1994-02-03 | 1999-08-10 | The Picower Institute For Medical Research | Compositions and methods for stimulating amyloid removal in amyloidogenic diseases using advanced glycosylation endproducts |
GB2335192A (en) | 1998-02-23 | 1999-09-15 | Exonhit Therapeutics Sa | Models for neurodegenerative diseases |
US5955317A (en) | 1993-01-25 | 1999-09-21 | Takeda Chemical Industries, Ltd. | Antibodies to β-amyloids or their derivatives and use thereof |
US5958883A (en) | 1992-09-23 | 1999-09-28 | Board Of Regents Of The University Of Washington Office Of Technology | Animal models of human amyloidoses |
US5985242A (en) | 1995-10-27 | 1999-11-16 | Praecis Pharmaceuticals, Inc. | Modulators of β-amyloid peptide aggregation comprising D-amino acids |
WO1999058564A1 (fr) | 1998-05-08 | 1999-11-18 | Norsk Hydro Asa | Mutants de dephasage de proteine de precurseur de beta-amyloide et d'ubiquitine-b et leur utilisation |
US5989566A (en) | 1995-06-30 | 1999-11-23 | American Cyanamid Company | Stable vaccine compositions for parenteral administration, a method for their use, and a process for their preparation |
WO1999060024A1 (fr) | 1998-05-21 | 1999-11-25 | The University Of Tennessee Research Corporation | Procede d'elimination d'amyloide a l'aide d'anticorps anti-amyloide |
WO1999060021A2 (fr) | 1998-05-19 | 1999-11-25 | Yeda Research And Development Co. Ltd. | Lymphocytes t actives, antigenes specifiques du systeme nerveux et leur utilisation |
US5994083A (en) | 1993-05-11 | 1999-11-30 | Istituto Di Recerche Di Biologia Molecolare P. Angeletti S.P.A. | Process for the preparation of immunogens or diagnostic reagents, and immunogens or diagnostic reagents thereby obtainable |
US6015662A (en) | 1996-01-23 | 2000-01-18 | Abbott Laboratories | Reagents for use as calibrators and controls |
US6022859A (en) | 1996-11-15 | 2000-02-08 | Wisconsin Alumni Research Foundation | Inhibitors of β-amyloid toxicity |
WO2000020027A2 (fr) | 1998-10-05 | 2000-04-13 | M & E Biotech A/S | Nouveaux procedes de vaccination therapeutique |
US6054297A (en) | 1991-06-14 | 2000-04-25 | Genentech, Inc. | Humanized antibodies and methods for making them |
WO2000023082A1 (fr) | 1998-10-19 | 2000-04-27 | Yeda Research And Development Co. Ltd. | Traitement du lupus erythemateux systemique par regulation negative de la reponse auto-immune a des autoantigenes |
US6057098A (en) | 1997-04-04 | 2000-05-02 | Biosite Diagnostics, Inc. | Polyvalent display libraries |
US6057367A (en) | 1996-08-30 | 2000-05-02 | Duke University | Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses |
WO2000026238A2 (fr) | 1998-11-04 | 2000-05-11 | D-Gen Limited | Materiaux biologiques et procedes utiles pour le diagnostic et le traitement de maladies |
WO2000043049A1 (fr) | 1999-01-19 | 2000-07-27 | Pharmacia & Upjohn Company | Emballage a base de polyethylene sterilise par rayonnement gamma |
WO2000043039A1 (fr) | 1999-01-22 | 2000-07-27 | Matthew John During | Traitement de troubles psychologiques a base de vaccin |
US6096318A (en) | 1973-05-07 | 2000-08-01 | The Ohio State University | Antigenically modified HCG polypeptides |
US6114133A (en) | 1994-11-14 | 2000-09-05 | Elan Pharmaceuticals, Inc. | Methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-β peptide (x-≧41) |
US6121022A (en) | 1995-04-14 | 2000-09-19 | Genentech, Inc. | Altered polypeptides with increased half-life |
WO2000068263A2 (fr) | 1999-05-05 | 2000-11-16 | Neurochem, Inc. | Peptides stereoselectifs antifibrillogenese et peptidomimetiques correspondants |
US6150091A (en) | 1996-03-06 | 2000-11-21 | Baylor College Of Medicine | Direct molecular diagnosis of Friedreich ataxia |
WO2000072880A2 (fr) | 1999-05-28 | 2000-12-07 | Neuralab Limited | Prevention et traitement de maladie amyloidogene |
WO2000072876A2 (fr) | 1999-06-01 | 2000-12-07 | Neuralab Limited | Prevention et traitement de maladies amyloidogenes |
WO2000072870A1 (fr) | 1999-06-01 | 2000-12-07 | Neuralab, Ltd. | Compositions de peptide a-beta et leurs procedes de production |
WO2000077178A1 (fr) | 1999-06-16 | 2000-12-21 | Boston Biomedical Research Institute | Temoin immunologique de niveaux de $g(b)-amyloide <i/in vivo> |
US6165745A (en) | 1992-04-24 | 2000-12-26 | Board Of Regents, The University Of Texas System | Recombinant production of immunoglobulin-like domains in prokaryotic cells |
US6175057B1 (en) | 1997-10-08 | 2001-01-16 | The Regents Of The University Of California | Transgenic mouse model of alzheimer's disease and cerebral amyloid angiopathy |
WO2001005355A2 (fr) | 1999-07-15 | 2001-01-25 | Genetics Institute, Inc. | Formulations d'il-11 |
WO2001010900A2 (fr) | 1999-08-04 | 2001-02-15 | University Of Southern California | PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6210671B1 (en) | 1992-12-01 | 2001-04-03 | Protein Design Labs, Inc. | Humanized antibodies reactive with L-selectin |
WO2001039796A2 (fr) | 1999-11-29 | 2001-06-07 | Neurochem Inc. | Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides |
WO2001042306A2 (fr) | 1999-12-08 | 2001-06-14 | Mindset Biopharmaceuticals (Usa), Inc. | Peptides chimeriques comme immunogenes, anticorps contre ces immunogenes et techniques d'immunisation utilisant ces peptides chimeriques ou ces anticorps |
US6262335B1 (en) | 1994-01-27 | 2001-07-17 | Johns Hopkins University | Transgenic mice expressing APP mutant at amino acids 717, 721 and 722 |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6270757B1 (en) | 1994-04-21 | 2001-08-07 | Genetics Institute, Inc. | Formulations for IL-11 |
US6277375B1 (en) | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
WO2001062284A2 (fr) | 2000-02-21 | 2001-08-30 | Pharmexa A/S | Nouvelle methode de regulation negative d'amyloide |
US20010018053A1 (en) | 1999-09-14 | 2001-08-30 | Mcmichael John | Methods for treating disease states comprising administration of low levels of antibodies |
WO2001062801A2 (fr) | 2000-02-24 | 2001-08-30 | Washington University | Anticorps humanises sequestrant un peptide a$g(b) |
US6284533B1 (en) | 1996-05-01 | 2001-09-04 | Avant Immunotherapeutics, Inc. | Plasmid-based vaccine for treating atherosclerosis |
US20010021769A1 (en) | 1996-11-05 | 2001-09-13 | Prusiner Stanley B. | Somatic cells with ablated PrP gene and methods of use |
US6303567B1 (en) | 1995-03-14 | 2001-10-16 | Praecis Pharmaceuticals, Inc . | Modulators of β-amyloid peptide aggregation comprising D-amino acids |
WO2001077167A2 (fr) | 2000-04-05 | 2001-10-18 | University Of Tennessee Research Corporation | Techniques d'etude, de diagnostic et de traitement d'amylose |
WO2001078777A2 (fr) | 2000-04-13 | 2001-10-25 | Mossman, Sally | COMPOSITIONS IMMUNOSTIMULANTES COMPRENANT UN PHOSPHATE D'AMINOALKYL GLUCOSAMINIDE ET DU QS-21 |
WO2001018169A3 (fr) | 1999-09-03 | 2001-11-22 | Univ Ramot | Agents et compositions et procedes utilisant lesdits agents et lesdites compositions pour le diagnostic et/ou le traitement ou la prevention des maladies formant des plaques. |
WO2001090182A2 (fr) | 2000-05-22 | 2001-11-29 | New York University | Peptides immunogenes synthetiques mais non-amyloidogenes homologues de beta-amyloide, destines a induire une reaction immunitaire contre les peptides beta-amyloide et les depots amyloides |
US6339068B1 (en) | 1997-05-20 | 2002-01-15 | University Of Iowa Research Foundation | Vectors and methods for immunization or therapeutic protocols |
EP1172378A1 (fr) | 2000-07-12 | 2002-01-16 | Richard Dr. Dodel | Anticorps humains anti-beta-amyloid et leur utilisation pour le traitement de la maladie d'Alzheimer |
WO2002003911A2 (fr) | 2000-07-07 | 2002-01-17 | Lars Lannfelt | Prevention et traitement de la maladie d'alzheimer |
US20020009445A1 (en) | 2000-07-12 | 2002-01-24 | Yansheng Du | Human beta-amyloid antibody and use thereof for treatment of alzheimer's disease |
WO2002021141A2 (fr) | 2000-09-06 | 2002-03-14 | Aventis Pharma S.A. | Procedes et compositions relatifs a des maladies associees a l'amyloide |
US6372716B1 (en) | 1994-04-26 | 2002-04-16 | Genetics Institute, Inc. | Formulations for factor IX |
WO2002034878A2 (fr) | 2000-10-26 | 2002-05-02 | Yeda Research And Development Co. Ltd. | Proteine precurseur de l'amyloide (app) et peptides derives de l'app inhibant la croissance de tumeurs et de metastases |
WO2002034777A1 (fr) | 2000-10-24 | 2002-05-02 | Chiesi Farmaceutici S.P.A. | Proteines de fusion utilisees comme traitements d'immunisation contre la maladie d'alzheimer |
US20020058267A1 (en) | 1997-04-16 | 2002-05-16 | American Home Products Corporation | Beta-amyloid peptide-binding proteins and polynucleotides encoding the same |
US6399314B1 (en) | 1999-12-29 | 2002-06-04 | American Cyanamid Company | Methods of detection of amyloidogenic proteins |
US20020086847A1 (en) | 1997-04-09 | 2002-07-04 | Mindset Biopharmaceuticals (Usa) | Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof |
US6417178B1 (en) | 1994-07-19 | 2002-07-09 | University Of Pittsburgh | Amyloid binding nitrogen-linked compounds for the antemortem diagnosis of alzheimer's disease, in vivo imaging and prevention of amyloid deposits |
US20020094335A1 (en) | 1999-11-29 | 2002-07-18 | Robert Chalifour | Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases |
US6432710B1 (en) | 1998-05-22 | 2002-08-13 | Isolagen Technologies, Inc. | Compositions for regenerating tissue that has deteriorated, and methods for using such compositions |
US20020133001A1 (en) | 2000-11-27 | 2002-09-19 | Praecis Pharmaceuticals Inc. | Therapeutic agents and methods of use thereof for treating an amyloidogenic disease |
US20020132268A1 (en) | 2000-12-27 | 2002-09-19 | Jui-Yoa Chang | Prion isomers, methods of making, methods of using, and compositions and products comprising prion isomers |
US20020160394A1 (en) | 2001-01-24 | 2002-10-31 | Bayer Corporation | Regulation of transthyretin to treat obesity |
WO2002088306A2 (fr) | 2001-04-30 | 2002-11-07 | Eli Lilly And Company | Anticorps humanises |
WO2002088307A2 (fr) | 2001-04-30 | 2002-11-07 | Eli Lilly And Company | Anticorps humanises |
US20020168377A1 (en) | 2001-04-19 | 2002-11-14 | Hermann Schaetzl | Prion protein dimers useful for vaccination |
WO2002096457A2 (fr) | 2001-05-31 | 2002-12-05 | Novartis Ag | Formulations liquides stable s |
US20020187157A1 (en) | 2000-02-21 | 2002-12-12 | Jensen Martin Roland | Novel method for down-regulation of amyloid |
US20020197258A1 (en) | 2001-06-22 | 2002-12-26 | Ghanbari Hossein A. | Compositions and methods for preventing protein aggregation in neurodegenerative diseases |
US20030009104A1 (en) | 2000-11-02 | 2003-01-09 | Hyman Bradley T. | In vivo multiphoton diagnostic detection and imaging of a neurodegenerative disease |
WO2003009817A2 (fr) | 2001-07-25 | 2003-02-06 | Protein Design Labs, Inc. | Formulation pharmaceutique lyophilisee stable d'anticorps igg |
WO2003016467A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b) |
WO2003016466A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Anticorps anti-$g(a)$g(b) |
WO2003015691A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Amelioration rapide des processus cognitifs dans les etats pathologiques lies a l'$g(a)$g(b) |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
WO2003020212A2 (fr) | 2001-08-29 | 2003-03-13 | Mayo Foundation For Medical Education And Research | Traitement pour des troubles du systeme nerveux central |
US20030054484A1 (en) | 1999-04-20 | 2003-03-20 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
US20030068325A1 (en) | 2001-05-25 | 2003-04-10 | Wang Chang Yi | Immunogenic peptide composition for the prevention and treatment of Altzheimers Disease |
US20030068316A1 (en) | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
US20030073655A1 (en) | 1997-04-09 | 2003-04-17 | Chain Daniel G. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
US20030092145A1 (en) | 2000-08-24 | 2003-05-15 | Vic Jira | Viral vaccine composition, process, and methods of use |
WO2003039485A2 (fr) | 2001-11-08 | 2003-05-15 | Protein Design Labs | Formulation pharmaceutique liquide stable d'anticorps igg |
WO2003051374A2 (fr) | 2001-12-17 | 2003-06-26 | New York State Office Of Mental Health | SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE |
US20030135035A1 (en) | 2001-08-09 | 2003-07-17 | Mark Shannon | Human ZZAP1 protein |
US20030147882A1 (en) | 1998-05-21 | 2003-08-07 | Alan Solomon | Methods for amyloid removal using anti-amyloid antibodies |
US6610493B1 (en) | 1993-06-17 | 2003-08-26 | Brigham And Women's Hospital | Screening compounds for the ability to alter the production of amyloid-β peptide |
WO2002046237A3 (fr) | 2000-12-06 | 2003-09-04 | Neuralab Ltd | Anticorps humanises reconnaissant le peptide amyloide beta |
US20030166558A1 (en) | 2001-11-21 | 2003-09-04 | New York University | Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid beta, prion protein, amylin, alpha-synuclein, or polyglutamine repeats for induction of an immune response thereto |
US20030166557A1 (en) | 2001-10-31 | 2003-09-04 | Board Of Regents, The University Of Texas System | SEMA3B inhibits tumor growth and induces apoptosis in cancer cells |
WO2003072036A2 (fr) | 2002-02-21 | 2003-09-04 | Duke University | Methodes therapeutiques utilisant des anticorps anti-cd22 |
WO2003077858A2 (fr) | 2002-03-12 | 2003-09-25 | Neuralab Limited | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
US20030202972A1 (en) | 1995-07-27 | 2003-10-30 | Genentech, Inc. | Protein formulation |
US20030207828A1 (en) | 1996-12-05 | 2003-11-06 | Tetsuyoshi Ishiwata | IgA nephropathy-related DNA |
WO2003105894A1 (fr) | 2002-06-14 | 2003-12-24 | Medimmune, Inc. | Preparations d'anticorps anti-vrs liquides stabilisees |
WO2004013172A2 (fr) | 2002-07-24 | 2004-02-12 | Innogenetics N.V. | Prevention, traitement et diagnostic de maladies associees a la formation et/ou a l'agregation de la beta-amyloide |
WO2004016282A1 (fr) | 2002-07-19 | 2004-02-26 | Cytos Biotechnology Ag | Matrices d'antigenes amyloides $g(b)1-6 |
US6710226B1 (en) | 1997-12-02 | 2004-03-23 | Neuralab Limited | Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics |
WO2004031400A2 (fr) | 2002-10-01 | 2004-04-15 | Northwestern University | Ligands diffusibles derives de l'amyloide beta (addl), substituts d'addl, molecules de liaison aux addl, et leurs utilisations |
US6727349B1 (en) | 1998-07-23 | 2004-04-27 | Millennium Pharmaceuticals, Inc. | Recombinant anti-CCR2 antibodies and methods of use therefor |
US20040081657A1 (en) | 1997-12-02 | 2004-04-29 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20040087777A1 (en) | 2000-12-06 | 2004-05-06 | Elan Pharmaceuticals, Inc. | Humanized antibodies that recognize beta amyloid peptide |
WO2004044204A2 (fr) | 2002-11-06 | 2004-05-27 | Institut Pasteur | Fragments variables d'anticorps de camelides a chaine unique et leurs applications pour le diagnostic et le traitement de pathologies diverses. |
US6743427B1 (en) | 1997-12-02 | 2004-06-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6750324B1 (en) | 1997-12-02 | 2004-06-15 | Neuralab Limited | Humanized and chimeric N-terminal amyloid beta-antibodies |
WO2004055164A2 (fr) | 2002-12-13 | 2004-07-01 | Abgenix, Inc. | Systeme et methode de stabilisation d'anticorps au moyen d'histidine |
US6761888B1 (en) | 2000-05-26 | 2004-07-13 | Neuralab Limited | Passive immunization treatment of Alzheimer's disease |
WO2004069182A2 (fr) | 2003-02-01 | 2004-08-19 | Neuralab Limited | Immunisation active permettant de produire des anticorps contre a-beta soluble |
WO2004071408A2 (fr) | 2003-02-10 | 2004-08-26 | Applied Molecular Evolution, Inc. | Molecules de liaison au peptide a$g(b) |
US6787129B1 (en) | 2003-01-13 | 2004-09-07 | Zenitech Llc | Castor polyester as gloss agents in anionic systems |
US6787637B1 (en) | 1999-05-28 | 2004-09-07 | Neuralab Limited | N-Terminal amyloid-β antibodies |
US20040197324A1 (en) | 2003-04-04 | 2004-10-07 | Genentech, Inc. | High concentration antibody and protein formulations |
US6824780B1 (en) | 1999-10-29 | 2004-11-30 | Genentech, Inc. | Anti-tumor antibody compositions and methods of use |
WO2004108895A2 (fr) | 2003-05-30 | 2004-12-16 | Neuralab Limited | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
US20040265919A1 (en) | 2003-05-22 | 2004-12-30 | Hugo Vanderstichele | Method for the prediction, diagnosis and differential diagnosis of Alzheimer's disease |
EP0921189B1 (fr) | 1997-11-14 | 2005-01-12 | Sankyo Company Limited | Animal transgénique comme modèle d'allergie et méthodes d'utilisation |
WO2005014041A2 (fr) | 2003-07-24 | 2005-02-17 | Novartis Ag | Substances et procedes pour le traitement des amyloses |
US20050059802A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Ltd | Prevention and treatment of amyloidogenic disease |
US20050059591A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
WO2005026211A2 (fr) | 2003-09-05 | 2005-03-24 | Eli Lilly And Company | Anticorps anti-ghreline |
US6875434B1 (en) | 1997-12-02 | 2005-04-05 | Neuralab Limited | Methods of treatment of Alzheimer's disease |
WO2005035753A1 (fr) | 2003-10-10 | 2005-04-21 | Chugai Seiyaku Kabushiki Kaisha | Anticorps a double specificite remplaçant une proteine fonctionnelle |
WO2005058940A2 (fr) | 2003-12-17 | 2005-06-30 | Wyeth | Conjugues porteurs de peptides immunogenes et procedes de production associes |
WO2005058941A2 (fr) | 2003-12-17 | 2005-06-30 | Elan Pharmaceuticals, Inc. | Conjugues porteurs de peptide immunogene a? les techniques de production de ces conjugues |
US6923964B1 (en) | 1997-12-02 | 2005-08-02 | Neuralab Limited | Active immunization of AScr for prion disorders |
US20050169925A1 (en) | 2002-02-20 | 2005-08-04 | Michael Bardroff | Anti-amyloid beta antibodies and their use |
US6933368B2 (en) | 1992-03-09 | 2005-08-23 | Protein Design Labs, Inc. | Increasing antibody affinity by altering glycosylation of immunoglobulin variable region |
US6936698B2 (en) | 1998-04-28 | 2005-08-30 | Smithkline Beecham | Monoclonal antibodies with reduced immunogenicity |
US20050214222A1 (en) | 2004-02-13 | 2005-09-29 | Mckinnon Stuart J | In vivo imaging of amyloid plaques in glaucoma using intravenous injectable dyes |
WO2005090315A1 (fr) | 2004-03-15 | 2005-09-29 | Janssen Pharmaceutica, N. V. | Nouveaux composes en tant que modulateurs de recepteurs d'opioides |
US20060057701A1 (en) | 2004-07-30 | 2006-03-16 | Arnon Rosenthal | Antibodies directed against amyloid-beta peptide and methods using same |
WO2006031653A2 (fr) | 2004-09-10 | 2006-03-23 | Wyeth | Anticorps anti-5t4 humanises et conjugues anticorps anti-5t4/calicheamicine |
US20060099206A1 (en) | 2004-10-05 | 2006-05-11 | Sinacore Martin S | Methods and compositions for improving recombinant protein production |
WO2006066171A1 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Anticorps amyloide ???? utilises afin d'ameliorer la cognition |
WO2006066049A2 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Anticorps humanises reconnaissant le peptide beta amyloide |
EP1321166B1 (fr) | 2001-12-21 | 2006-07-05 | Ethicon Inc. | Electrode de retour de masse déployable et méthode d'utilisation |
US20060153772A1 (en) | 2004-12-15 | 2006-07-13 | Wyeth | Contextual fear conditioning for predicting immunotherapeutic efficacy |
US20060160161A1 (en) | 2004-10-26 | 2006-07-20 | Elan Pharmaceuticals, Inc. | Methods for assessing antibodies to neurodegenerative disease-associated antigens |
WO2006081587A2 (fr) | 2005-01-28 | 2006-08-03 | Wyeth | Formulations polypeptidiques liquides stabilisees |
WO2006083689A2 (fr) | 2005-01-28 | 2006-08-10 | Elan Pharma International Limited | Preparation d'anticorps anti-a$g(b) |
US20060182321A1 (en) | 2003-07-07 | 2006-08-17 | Agency For Science, Technology And Research | Method and apparatus for extracting third ventricle information |
US20060198851A1 (en) | 2004-12-15 | 2006-09-07 | Guriq Basi | Humanized Abeta antibodies for use in improving cognition |
US20060210964A1 (en) | 1999-07-01 | 2006-09-21 | Hyslop Paul A | Prevention and treatment of amyloid-associated disorders |
US7112661B1 (en) | 1998-10-30 | 2006-09-26 | The Research Foundation Of State University Of New York | Variable heavy chain and variable light chain regions of antibodies to human platelet glycoprotein Ib alpha |
US20060234912A1 (en) | 2003-10-08 | 2006-10-19 | Wang Yu T | Methods for modulating neuronal responses |
US20060240486A1 (en) | 2004-12-15 | 2006-10-26 | Johnson-Wood Kelly L | Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies |
WO2006121656A2 (fr) | 2005-05-05 | 2006-11-16 | Merck & Co., Inc. | Compositions a base de conjugues peptidiques et methodes destinees a la prevention et au traitement de la maladie d'alzheimer |
US7147851B1 (en) | 1996-08-15 | 2006-12-12 | Millennium Pharmaceuticals, Inc. | Humanized immunoglobulin reactive with α4β7 integrin |
US20070021454A1 (en) | 2005-07-18 | 2007-01-25 | Coburn Craig A | Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease |
US20070072307A1 (en) | 2005-06-17 | 2007-03-29 | Ranganathan Godavarti | Methods of purifying Fc region containing proteins |
US20070154480A1 (en) | 1998-04-07 | 2007-07-05 | Schenk Dale B | Humanized antibodies that recognize beta amyloid peptide |
US20070196375A1 (en) | 1999-02-24 | 2007-08-23 | Tact Ip, Llc | Methods to facilitate transmission of large molecules across the blood-brain, blood-eye, and blood-nerve barriers |
US20070238154A1 (en) | 2000-12-06 | 2007-10-11 | Elan Pharma International Limited | Humanized antibodies that recognize beta-amyloid peptide |
WO2008011348A2 (fr) | 2006-07-14 | 2008-01-24 | Ac Immune S.A. | Anticorps humanisé |
US20080031954A1 (en) | 2005-11-10 | 2008-02-07 | Daniel Paris | Modulation of angiogenesis by a-beta peptide fragments |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US20080219931A1 (en) | 2004-07-02 | 2008-09-11 | University Of Pittsburgh | Amyloid Imaging as a Surrogate Marker for Efficacy of Anti-Amyloid Therapies |
WO2008114801A1 (fr) | 2007-03-12 | 2008-09-25 | National Institute Of Radiological Sciences | Visualisation par tomographie par émission de positons d'une neuro-inflammation associée aux amyloïdes dans le cerveau |
WO2008131298A2 (fr) | 2007-04-18 | 2008-10-30 | Elan Pharma International Limited | Prévention et traitement d'angiopathie amyloïde cérébrale |
WO2009017467A1 (fr) | 2007-07-27 | 2009-02-05 | Elan Pharma International Limited | Traitement de maladies amyloïdogéniques |
WO2009052439A2 (fr) | 2007-10-17 | 2009-04-23 | Elan Pharma International Limited | Régimes immunothérapeutiques dépendant du statut de l'apoe |
US20090142270A1 (en) | 2007-04-18 | 2009-06-04 | Elan Pharma International Limited | Prevention and treatment of cerebral amyloid angiopathy |
US7625550B2 (en) | 2001-09-10 | 2009-12-01 | Anticancer, Inc. | Enhanced resolution of tumor metastasis using a skin flap model |
WO2010033861A1 (fr) | 2008-09-18 | 2010-03-25 | Cedars-Sinai Medical Center | Procédé optique pour la détection de la maladie d'alzheimer |
WO2010044803A1 (fr) | 2008-10-17 | 2010-04-22 | Elan Pharma International Limited | Traitement de maladies amyloïdogènes |
US7928203B2 (en) | 2007-12-28 | 2011-04-19 | Elan Pharmaceuticals, Inc. | Chimeric, humanized, or human antibody 2A4 |
US20110142824A1 (en) | 2006-03-30 | 2011-06-16 | Glaxo Group Limited | Antibodies Against Amyloid-Beta Peptide |
WO2011106732A1 (fr) | 2010-02-25 | 2011-09-01 | Wyeth Llc | Surveillance pet d'une immunothérapie dirigée contre l'aβ |
US20110229413A1 (en) | 2006-04-18 | 2011-09-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
WO2011133919A1 (fr) | 2010-04-22 | 2011-10-27 | Janssen Alzheimer Immunotherapy | Utilisation de tau pour un suivi d'immunothérapie |
EP1950991B1 (fr) | 2005-10-04 | 2016-09-21 | Huawei Technologies Co., Ltd. | Dispositif de station mobile, système et procede pour le mappage de bande de frequences utilisée par le dispositif de station mobile |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19927554C2 (de) * | 1999-06-16 | 2002-12-19 | Inst Mikrotechnik Mainz Gmbh | Mikromischer |
-
2005
- 2005-12-15 PE PE2005001469A patent/PE20061329A1/es not_active Application Discontinuation
- 2005-12-15 JP JP2007546940A patent/JP2008523815A/ja not_active Withdrawn
- 2005-12-15 AR ARP050105296A patent/AR052051A1/es not_active Application Discontinuation
- 2005-12-15 TW TW094144715A patent/TW200635607A/zh unknown
- 2005-12-15 US US11/303,478 patent/US8916165B2/en not_active Expired - Fee Related
- 2005-12-15 ES ES05854354T patent/ES2434732T3/es active Active
- 2005-12-15 EP EP05854354.7A patent/EP1838348B1/fr active Active
- 2005-12-15 CA CA2590337A patent/CA2590337C/fr not_active Expired - Fee Related
- 2005-12-15 WO PCT/US2005/045614 patent/WO2006066089A1/fr active Application Filing
- 2005-12-20 UY UY29284A patent/UY29284A1/es not_active Application Discontinuation
-
2008
- 2008-04-03 HK HK08103792.6A patent/HK1109585A1/xx not_active IP Right Cessation
-
2011
- 2011-09-20 JP JP2011204891A patent/JP2012024098A/ja active Pending
Patent Citations (557)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6096318A (en) | 1973-05-07 | 2000-08-01 | The Ohio State University | Antigenically modified HCG polypeptides |
US4816397A (en) | 1983-03-25 | 1989-03-28 | Celltech, Limited | Multichain polypeptides or proteins and processes for their production |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5620844A (en) | 1984-03-07 | 1997-04-15 | New York Blood, Inc. | Assays for detecting hepatitis B virus envelope antigens or antibodies thereto and diagnostic test kits for use in performing the assays |
US5417986A (en) | 1984-03-16 | 1995-05-23 | The United States Of America As Represented By The Secretary Of The Army | Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres |
US5208036A (en) | 1985-01-07 | 1993-05-04 | Syntex (U.S.A.) Inc. | N-(ω, (ω-1)-dialkyloxy)- and N-(ω, (ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US4666829A (en) | 1985-05-15 | 1987-05-19 | University Of California | Polypeptide marker for Alzheimer's disease and its use for diagnosis |
WO1987002671A1 (fr) | 1985-11-01 | 1987-05-07 | International Genetic Engineering, Inc. | Assemblage modulaire de genes d'anticorps, anticorps ainsi prepares et utilisation |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4713366A (en) | 1985-12-04 | 1987-12-15 | The Ohio State University Research Foundation | Antigenic modification of polypeptides |
US5096706A (en) | 1986-03-25 | 1992-03-17 | National Research Development Corporation | Antigen-based treatment for adiposity |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
WO1987006838A1 (fr) | 1986-05-05 | 1987-11-19 | Praxis Biologics, Inc. | Conjugues immunogeniques |
JPS62267297A (ja) | 1986-05-15 | 1987-11-19 | Tokyo Met Gov Seishin Igaku Sogo Kenkyusho | 老人斑反応性モノクロ−ナル抗体、それを産生する細胞株及び該モノクロ−ナル抗体の製造方法 |
US5278049A (en) | 1986-06-03 | 1994-01-11 | Incyte Pharmaceuticals, Inc. | Recombinant molecule encoding human protease nexin |
US5231170A (en) | 1986-08-27 | 1993-07-27 | Paul Averback | Antibodies to dense microspheres |
US5220013A (en) | 1986-11-17 | 1993-06-15 | Scios Nova Inc. | DNA sequence useful for the detection of Alzheimer's disease |
US5187153A (en) | 1986-11-17 | 1993-02-16 | Scios Nova Inc. | Methods of treatment using Alzheimer's amyloid polypeptide derivatives |
US4879213A (en) | 1986-12-05 | 1989-11-07 | Scripps Clinic And Research Foundation | Synthetic polypeptides and antibodies related to Epstein-Barr virus early antigen-diffuse |
EP0276723B1 (fr) | 1987-01-30 | 1993-12-08 | Bayer Ag | Précurseur protéinique de polypeptide-APC, ADN le codant et utilisation diagnostique de cet ADN et de cette protéine |
US4912206A (en) | 1987-02-26 | 1990-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | CDNA clone encoding brain amyloid of alzheimer's disease |
US5624821A (en) | 1987-03-18 | 1997-04-29 | Scotgen Biopharmaceuticals Incorporated | Antibodies with altered effector functions |
US5648260A (en) | 1987-03-18 | 1997-07-15 | Scotgen Biopharmaceuticals Incorporated | DNA encoding antibodies with altered effector functions |
WO1988007089A1 (fr) | 1987-03-18 | 1988-09-22 | Medical Research Council | Anticorps alteres |
EP0285159A1 (fr) | 1987-03-31 | 1988-10-05 | Suntory Limited | Anticorps monoclonal contre une protéine humaine apparentée à l'amyloide |
US4883666A (en) | 1987-04-29 | 1989-11-28 | Massachusetts Institute Of Technology | Controlled drug delivery system for treatment of neural disorders |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
US5583112A (en) | 1987-05-29 | 1996-12-10 | Cambridge Biotech Corporation | Saponin-antigen conjugates and the use thereof |
EP0359783B1 (fr) | 1987-06-24 | 1995-11-29 | Autoimmune, Inc. | Traitement de maladies auto-immunitaires par administration orale d'auto-antigenes |
US5571499A (en) | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
US5641474A (en) | 1987-06-24 | 1997-06-24 | Autoimmune, Inc. | Prevention of autoimmune diseases by aerosol administration of autoantigens |
EP0666080A1 (fr) | 1987-06-24 | 1995-08-09 | Brigham & Women's Hospital | Traitement de maladies auto-immunitaires par administration orale d'auto-antigènes |
US5645820A (en) | 1987-06-24 | 1997-07-08 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
US5869093A (en) | 1987-06-24 | 1999-02-09 | Autoimmune Inc. | Treatment of immune diseases by oral administration of autoantigens |
US5733547A (en) | 1987-06-24 | 1998-03-31 | Autoimmune, Inc. | Treatment of autoimmune arthritis by oral administration of type I or type III collagen |
US5849298A (en) | 1987-06-24 | 1998-12-15 | Autoimmune Inc. | Treatment of multiple sclerosis by oral administration of bovine myelin |
US5641473A (en) | 1987-06-24 | 1997-06-24 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
US5869054A (en) | 1987-06-24 | 1999-02-09 | Autoimmune Inc. | Treatment of multiple sclerosis by oral administration of autoantigens |
WO1988010120A1 (fr) | 1987-06-24 | 1988-12-29 | Brigham And Women's Hospital | Traitement de maladies auto-immunitaires par administration orale d'auto-antigenes |
US5571500A (en) | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases through administration by inhalation of autoantigens |
WO1989001343A1 (fr) | 1987-08-17 | 1989-02-23 | The Regents Of The University Of California | Anticorps cationises administres a travers la barriere sang-cerveau |
US5004697A (en) | 1987-08-17 | 1991-04-02 | Univ. Of Ca | Cationized antibodies for delivery through the blood-brain barrier |
US4966753A (en) | 1987-08-18 | 1990-10-30 | Molecular Rx, Inc. | Immunotherapeutic methods and compositions employing antigens characteristic of malignant neoplasms |
US5677425A (en) | 1987-09-04 | 1997-10-14 | Celltech Therapeutics Limited | Recombinant antibody |
EP0440619B1 (fr) | 1987-10-08 | 1996-01-24 | THE McLEAN HOSPITAL CORPORATION | Anticorps agissant sur un peptide de l'amyloide de sequence a4 |
US5231000A (en) | 1987-10-08 | 1993-07-27 | The Mclean Hospital | Antibodies to A4 amyloid peptide |
WO1989006242A1 (fr) | 1987-10-08 | 1989-07-13 | The Mclean Hospital Corporation | Anticorps agissant sur un peptide de l'amyloide de sequence a4 |
WO1989003687A1 (fr) | 1987-10-23 | 1989-05-05 | Genetics Institute, Inc. | Composition et procede de traitement des cancers caracterises par la surexpression du proto-oncogene c-fms |
WO1989006689A1 (fr) | 1988-01-13 | 1989-07-27 | The Mclean Hospital Corporation | Constructions genetiques renfermant le gene amyloide cerebral d'alzheimer |
GB2220211A (en) | 1988-06-29 | 1990-01-04 | Ribi Immunochem Research Inc | Modified lipopolysaccharides |
US5576184A (en) | 1988-09-06 | 1996-11-19 | Xoma Corporation | Production of chimeric mouse-human antibodies with specificity to human tumor antigens |
WO1990005142A1 (fr) | 1988-11-10 | 1990-05-17 | Imperial Cancer Research Technology Ltd. | Polypeptides |
WO1990007861A1 (fr) | 1988-12-28 | 1990-07-26 | Protein Design Labs, Inc. | IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2 |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693761A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Polynucleotides encoding improved humanized immunoglobulins |
US6180370B1 (en) | 1988-12-28 | 2001-01-30 | Protein Design Labs, Inc. | Humanized immunoglobulins and methods of making the same |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5227159A (en) | 1989-01-31 | 1993-07-13 | Miller Richard A | Anti-idiotype antibodies reactive with shared idiotopes expressed by B cell lymphomas and autoantibodies |
US5262332A (en) | 1989-04-05 | 1993-11-16 | Brigham And Women's Hospital | Diagnostic method for Alzheimer's disease: examination of non-neural tissue |
EP0391714A2 (fr) | 1989-04-05 | 1990-10-10 | BRIGHAM & WOMEN'S HOSPITAL | Procédé pour la détection de la maladie d'Alzheimer: examen du tissu non-nerval |
WO1990012871A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal sv17-6e10 specifique de la proteine amyloide cerebrovasculaire |
WO1990012870A1 (fr) | 1989-04-14 | 1990-11-01 | Research Foundation For Mental Hygiene, Inc. | Anticorps monoclonal du peptide amyloide |
WO1990014837A1 (fr) | 1989-05-25 | 1990-12-13 | Chiron Corporation | Composition d'adjuvant comprenant une emulsion de gouttelettes d'huile d'une taille inferieure au micron |
WO1990014840A1 (fr) | 1989-06-06 | 1990-12-13 | California Biotechnology Inc. | Proteine d'amyloide d'alzheimer recombinante |
US5866129A (en) | 1989-06-21 | 1999-02-02 | Tanox Biosystems, Inc. | Method of producing an antibody with a peptide corresponding to membrane-bound IgA |
WO1991008760A1 (fr) | 1989-12-20 | 1991-06-27 | Brigham And Women's Hospital | Traitement ameliore de maladies auto-immunes par administration par aerosol d'auto-antigenes |
EP0506785B1 (fr) | 1989-12-20 | 2000-03-15 | Autoimmune, Inc. | Traitement ameliore de maladies auto-immunes par administration par aerosol d'auto-antigenes |
US20050123534A1 (en) | 1989-12-21 | 2005-06-09 | Celltech R&D Limited | Humanised antibodies |
WO1991009967A1 (fr) | 1989-12-21 | 1991-07-11 | Celltech Limited | Anticorps humanises |
US20050136054A1 (en) | 1989-12-21 | 2005-06-23 | Celltech R&D Limited | Humanised antibodies |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US20030039645A1 (en) | 1989-12-21 | 2003-02-27 | Adair John Robert | Humanised antibodies |
US6632927B2 (en) | 1989-12-21 | 2003-10-14 | Celltech Therapeutics Limited | Humanized antibodies |
EP0626390A1 (fr) | 1989-12-21 | 1994-11-30 | Celltech Therapeutics Limited | Anticorps humanisés |
EP0620276A1 (fr) | 1989-12-21 | 1994-10-19 | Celltech Therapeutics Limited | Anticorps humanisés |
WO1991010741A1 (fr) | 1990-01-12 | 1991-07-25 | Cell Genesys, Inc. | Generation d'anticorps xenogeniques |
WO1991012816A1 (fr) | 1990-03-02 | 1991-09-05 | Autoimmune, Inc. | Amelioration de la regulation reductrice de maladies autoimmunes par administration orale d'autoantigenes |
EP0594607B1 (fr) | 1990-03-02 | 1997-08-27 | Autoimmune, Inc. | Amelioration de la regulation reductrice de maladies autoimmunes par administration orale ou enterale d'autoantigenes |
EP0782859A1 (fr) | 1990-03-02 | 1997-07-09 | Autoimmune, Inc. | Amélioration de la régulation reductrice de maladies autoimmunes par administration orale d'autoantigènes |
EP0451700A1 (fr) | 1990-04-10 | 1991-10-16 | Miles Inc. | Minigènes APP recombinants pour l'expression dans des souris transgéniques comme modèles de la maladie d'Alzheimer |
US5270165A (en) | 1990-04-24 | 1993-12-14 | The Reagents Of The University Of California | Method of diagnosis of amyloidoses |
WO1991016928A1 (fr) | 1990-04-27 | 1991-11-14 | Celltech Limited | ANTICORPS ANTI-MOLECULE 1 d'ADHERENCE INTERCELLULAIRE CHIMERIQUE ADAPTES AU MODELE HUMAIN, PROCEDE DE PREPARATION ET D'UTILISATION |
US5851996A (en) | 1990-04-27 | 1998-12-22 | Milkhaus Laboratory, Inc. | Materials and methods for treatment of plaquing diseases |
WO1991016819A1 (fr) | 1990-04-27 | 1991-11-14 | Molecular Rx., Inc. | Procede et composition servant a traiter des etats pathologiques du systeme nerveux central associes a la proteine beta amyloide anormale |
US5753624A (en) | 1990-04-27 | 1998-05-19 | Milkhaus Laboratory, Inc. | Materials and methods for treatment of plaquing disease |
EP0526511B1 (fr) | 1990-04-27 | 1997-05-28 | MCMICHAEL, John | Procede et composition servant a traiter des etats pathologiques du systeme nerveux central associes a la proteine beta amyloide anormale |
WO1991017271A1 (fr) | 1990-05-01 | 1991-11-14 | Affymax Technologies N.V. | Procedes de triage de banques d'adn recombine |
WO1991019810A1 (fr) | 1990-06-15 | 1991-12-26 | California Biotechnology Inc. | Mammifere transgenique non humain presentant la pathologie de formation d'amyloides de la maladie d'alzheimer |
US5387742A (en) | 1990-06-15 | 1995-02-07 | Scios Nova Inc. | Transgenic mice displaying the amyloid-forming pathology of alzheimer's disease |
WO1991019795A1 (fr) | 1990-06-19 | 1991-12-26 | Immuvax | Variantes de virus non pathognes |
WO1992001059A1 (fr) | 1990-07-05 | 1992-01-23 | Celltech Limited | Anticorps diriges contre l'antigene carcino-embryonnaire (cea) et a greffe de zones determinant la complementarite (cdr) et production de ces anticorps |
WO1992001047A1 (fr) | 1990-07-10 | 1992-01-23 | Cambridge Antibody Technology Limited | Procede de production de chainon de paires a liaison specifique |
US5780587A (en) | 1990-08-24 | 1998-07-14 | President And Fellows Of Harvard College | Compounds and methods for inhibiting β-protein filament formation and neurotoxicity |
US5773007A (en) | 1990-09-17 | 1998-06-30 | National Research Council Of Canada | Vaccine compositions |
US5702906A (en) | 1990-09-25 | 1997-12-30 | Genentech, Inc. | Antibodies to neurotrophic factor-4 (NT-4) |
WO1992006187A1 (fr) | 1990-09-28 | 1992-04-16 | The Upjohn Company | Animaux transgeniques porteurs d'un gene de precurseur amyloide d'alzheimer |
WO1992005793A1 (fr) | 1990-10-05 | 1992-04-16 | Medarex, Inc. | Immunostimulation ciblee induite par des reactifs bispecifiques |
WO1992006708A1 (fr) | 1990-10-15 | 1992-04-30 | Brigham And Women's Hospital | Traitement de maladies auto-immunes par administration orale d'auto-antigenes |
WO1992007944A1 (fr) | 1990-10-26 | 1992-05-14 | Lynxvale Limited | Vecteur de la vaccine, genes de la vaccine et leurs produits d'expression |
WO1992013069A1 (fr) | 1991-01-21 | 1992-08-06 | Imperial College Of Science, Technology & Medicine | Test et modele pour la maladie d'alzheimer |
WO1992015330A1 (fr) | 1991-03-01 | 1992-09-17 | Rhône Merieux | Procede d'immunoneutralisation anti-lhrh des animaux domestiques males non castres et peptide pour cela |
US5192753A (en) | 1991-04-23 | 1993-03-09 | Mcgeer Patrick L | Anti-rheumatoid arthritic drugs in the treatment of dementia |
US5245015A (en) | 1991-04-26 | 1993-09-14 | Tanox Biosystems, Inc. | Monoclonal antibodies which neutralize HIV-1 through reaction with a conformational epitope in vitro |
WO1992019267A1 (fr) | 1991-05-08 | 1992-11-12 | Schweiz. Serum- & Impfinstitut Bern | Virosomes de la grippe reconstitues immunostimulants et immunopotentialisants et vaccins en contenant |
US6407213B1 (en) | 1991-06-14 | 2002-06-18 | Genentech, Inc. | Method for making humanized antibodies |
US6639055B1 (en) | 1991-06-14 | 2003-10-28 | Genentech, Inc. | Method for making humanized antibodies |
US6054297A (en) | 1991-06-14 | 2000-04-25 | Genentech, Inc. | Humanized antibodies and methods for making them |
WO1992022653A1 (fr) | 1991-06-14 | 1992-12-23 | Genentech, Inc. | Procede de production d'anticorps humanises |
WO1993002189A1 (fr) | 1991-07-18 | 1993-02-04 | The Regents Of The University Of California | Modeles animaux transgeniques pour l'etude de la maladie d'alzheimer |
EP0597101A1 (fr) | 1991-07-20 | 1994-05-18 | Hagiwara, Yoshihide | Preparation a anticorps monoclonal humain stabilise |
US5837473A (en) | 1991-08-13 | 1998-11-17 | President And Fellows Of Harvard College | Methods of screening for agents affecting the deposition of β-amyloid peptides on amyloid plaques in human tissue |
WO1993004194A1 (fr) | 1991-08-13 | 1993-03-04 | Regents Of The University Of Minnesota | Peptide meta-amyloide marque et depistage de la maladie d'alzheimer |
US5837268A (en) | 1991-10-16 | 1998-11-17 | University Of Saskatchewan | GnRH-leukotoxin chimeras |
WO1993012227A1 (fr) | 1991-12-17 | 1993-06-24 | Genpharm International, Inc. | Animaux transgeniques non humains capables de produire des anticorps heterologues |
WO1993014200A1 (fr) | 1992-01-07 | 1993-07-22 | Tsi Corporation | Modeles d'animaux transgeniques utilises pour tester des traitements potentiels relatifs a la maladie d'alzheimer |
US5679348A (en) | 1992-02-03 | 1997-10-21 | Cedars-Sinai Medical Center | Immunotherapy for recurrent HSV infections |
WO1993015760A1 (fr) | 1992-02-11 | 1993-08-19 | U.S. Government, As Represented By The Secretary Of The Army | Structure immunogene a double vecteur |
EP0911036A2 (fr) | 1992-02-11 | 1999-04-28 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Structure immunogene à double vecteur |
US5955079A (en) | 1992-02-11 | 1999-09-21 | Henry Jackson Foundation For The Advancement Of Military Medicine | Dual carrier immunogenic construct |
US5585100A (en) | 1992-02-11 | 1996-12-17 | Henry Jackson Foundation | Dual carrier immunogenic construct |
WO1993016724A1 (fr) | 1992-02-28 | 1993-09-02 | Autoimmune, Inc. | Suppression de maladies auto-immunes par des antigenes en attente |
US6933368B2 (en) | 1992-03-09 | 2005-08-23 | Protein Design Labs, Inc. | Increasing antibody affinity by altering glycosylation of immunoglobulin variable region |
EP0561087B1 (fr) | 1992-03-20 | 1999-08-04 | N.V. Innogenetics S.A. | Forme mutée du gène de la protéine du précurseur beta-amyloide |
US5721130A (en) | 1992-04-15 | 1998-02-24 | Athena Neurosciences, Inc. | Antibodies and fragments thereof which bind the carboxyl-terminus of an amino-terminal fragment of βAPP |
US5441870A (en) | 1992-04-15 | 1995-08-15 | Athena Neurosciences, Inc. | Methods for monitoring cellular processing of β-amyloid precursor protein |
US5891991A (en) | 1992-04-20 | 1999-04-06 | The General Hospital Corporation | Amyloid precursor-like protein and uses thereof |
US6165745A (en) | 1992-04-24 | 2000-12-26 | Board Of Regents, The University Of Texas System | Recombinant production of immunoglobulin-like domains in prokaryotic cells |
WO1993021950A1 (fr) | 1992-04-28 | 1993-11-11 | Medeva Holdings Bv | Compositions de vaccin a administration par la muqueuse |
EP0639081B1 (fr) | 1992-04-28 | 1999-11-03 | Medeva Holdings B.V. | Compositions de vaccin a administration par la muqueuse |
US5601827A (en) | 1992-06-18 | 1997-02-11 | President And Fellows Of Harvard College | Diphtheria toxin vaccines |
WO1994000153A1 (fr) | 1992-06-25 | 1994-01-06 | Smithkline Beecham Biologicals (S.A.) | Composition vaccinale contenant des adjuvants |
US5837672A (en) | 1992-07-10 | 1998-11-17 | Athena Neurosciences, Inc. | Methods and compositions for the detection of soluble β-amyloid peptide |
US5766846A (en) | 1992-07-10 | 1998-06-16 | Athena Neurosciences | Methods of screening for compounds which inhibit soluble β-amyloid peptide production |
US6284221B1 (en) | 1992-07-10 | 2001-09-04 | Elan Pharmaceuticals, Inc. | Method for identifying β-amyloid peptide production inhibitors |
US5593846A (en) | 1992-07-10 | 1997-01-14 | Athena Neurosciences | Methods for the detection of soluble β-amyloid peptide |
WO1994001772A1 (fr) | 1992-07-13 | 1994-01-20 | The Children's Medical Center Corporation | CRIBLAGE DE TRAITEMENTS DE LA MALADIE D'ALZHEIMER SUR LA BASE DE LA PRODUCTION DE β-AMYLOIDE |
WO1994003208A1 (fr) | 1992-07-30 | 1994-02-17 | Yeda Research And Development Company Ltd. | Conjugues d'antigenes faiblement immunogenes et porteurs de peptides synthetiques et vaccins les contenant |
EP0652962B1 (fr) | 1992-07-31 | 1998-12-16 | Medeva Holdings B.V. | Expression de proteines recombinantes fusionnees dans des bacteries attenuees |
EP0863211A1 (fr) | 1992-07-31 | 1998-09-09 | Medeva Holdings B.V. | Expression de protéines recombinantes fusionnées dans des bactéries attenuées |
WO1994003615A1 (fr) | 1992-07-31 | 1994-02-17 | Medeva Holdings B.V. | Expression de proteines recombinantes fusionnees dans des bacteries attenuees |
WO1994005311A1 (fr) | 1992-08-27 | 1994-03-17 | Deakin Research Limited | Analogues peptidiques de synthese a modifications retro, inverse ou retro-inverse |
US6261569B1 (en) | 1992-08-27 | 2001-07-17 | Deakin Research Limited | Retro-, inverso- and retro-inverso synthetic peptide analogues |
US5958883A (en) | 1992-09-23 | 1999-09-28 | Board Of Regents Of The University Of Washington Office Of Technology | Animal models of human amyloidoses |
WO1994009364A1 (fr) | 1992-10-13 | 1994-04-28 | Duke University | Procede permettant d'inhiber la liaison de la proteine precurseur d'amyloide a la proteine beta-amyloide |
WO1994010569A1 (fr) | 1992-10-26 | 1994-05-11 | Schenk Dale B | PROCEDES ET COMPOSITIONS VISANT A DETECTER UN PEPTIDE β-AMYLOIDE SOLUBLE |
US5605811A (en) | 1992-10-26 | 1997-02-25 | Athena Neurosciences, Inc. | Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein |
WO1994009823A1 (fr) | 1992-11-03 | 1994-05-11 | Oravax, Inc. | Vaccin a base d'urease contre l'infection due a l'helicobacter |
US6210671B1 (en) | 1992-12-01 | 2001-04-03 | Protein Design Labs, Inc. | Humanized antibodies reactive with L-selectin |
WO1994016731A1 (fr) | 1993-01-22 | 1994-08-04 | Sloan-Kettering Institute For Cancer Research | Vaccins de conjugue ganglioside-klh avec qs-21 |
US5750349A (en) | 1993-01-25 | 1998-05-12 | Takeda Chemical Industries Ltd. | Antibodies to β-amyloids or their derivatives and use thereof |
EP0683234A1 (fr) | 1993-01-25 | 1995-11-22 | Takeda Chemical Industries, Ltd. | ANTICORPS DIRIGE CONTRE LE $g(b)-AMYLOIDE OU UN DERIVE DE CE DERNIER ET SON UTILISATION |
US5955317A (en) | 1993-01-25 | 1999-09-21 | Takeda Chemical Industries, Ltd. | Antibodies to β-amyloids or their derivatives and use thereof |
WO1994017197A1 (fr) | 1993-01-25 | 1994-08-04 | Takeda Chemical Industries, Ltd. | ANTICORPS DIRIGE CONTRE LE β-AMYLOIDE OU UN DERIVE DE CE DERNIER ET SON UTILISATION |
US5358708A (en) | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
US5472693A (en) | 1993-02-16 | 1995-12-05 | The Dow Chemical Company | Family of anti-carcinoembryonic antigen chimeric antibodies |
US5514548A (en) | 1993-02-17 | 1996-05-07 | Morphosys Gesellschaft Fur Proteinoptimerung Mbh | Method for in vivo selection of ligand-binding proteins |
EP0613007A2 (fr) | 1993-02-22 | 1994-08-31 | Eli Lilly And Company | Analyse pharmaceutique et anticorps |
US5733548A (en) | 1993-03-17 | 1998-03-31 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Immunogenic chimeras comprising nucleic acid sequences encoding endoplasmic reticulum signal sequence peptides and at least one other peptide, and their uses in vaccines and disease treatments |
WO1994021288A1 (fr) | 1993-03-18 | 1994-09-29 | Cytimmune Sciences, Inc. | Composition et methode d'abaissement de la toxicite de facteurs biologiquement actifs |
US5776468A (en) | 1993-03-23 | 1998-07-07 | Smithkline Beecham Biologicals (S.A.) | Vaccine compositions containing 3-0 deacylated monophosphoryl lipid A |
EP0616814A1 (fr) | 1993-03-26 | 1994-09-28 | Bristol-Myers Squibb Company | Compositions à libération contrôlée de TGF-bêta biologiquement actif |
US5994083A (en) | 1993-05-11 | 1999-11-30 | Istituto Di Recerche Di Biologia Molecolare P. Angeletti S.P.A. | Process for the preparation of immunogens or diagnostic reagents, and immunogens or diagnostic reagents thereby obtainable |
US5723130A (en) | 1993-05-25 | 1998-03-03 | Hancock; Gerald E. | Adjuvants for vaccines against respiratory syncytial virus |
WO1994028412A1 (fr) | 1993-05-28 | 1994-12-08 | The Miriam Hospital | Composition et procede d'imagerie in vivo de depots d'amyloide |
WO1994029459A1 (fr) | 1993-06-04 | 1994-12-22 | Whitehead Institute For Biomedical Research | Proteines du stress et leurs utilisations |
US6610493B1 (en) | 1993-06-17 | 2003-08-26 | Brigham And Women's Hospital | Screening compounds for the ability to alter the production of amyloid-β peptide |
US5464823A (en) | 1993-07-20 | 1995-11-07 | The Regents Of The University Of California | Mammalian antibiotic peptides |
WO1995004151A2 (fr) | 1993-07-30 | 1995-02-09 | Medeva Holdings B.V. | Compositions vaccinales comprenant des proteines de fusion tetc de recombinaison |
WO1995005393A2 (fr) | 1993-08-18 | 1995-02-23 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Peptides liant et neturalisant les lipopolysaccharides |
AU707083B2 (en) | 1993-08-26 | 1999-07-01 | Bavarian Nordic Inc. | Inducing antibody response against self-proteins with the aid of foreign T-cell epitopes |
WO1995005849A1 (fr) | 1993-08-26 | 1995-03-02 | Mouritsen & Elsner A/S | Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes |
EP0752886B1 (fr) | 1993-08-26 | 1998-01-28 | M&E BIOTECH A/S | Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes |
WO1995005853A1 (fr) | 1993-08-26 | 1995-03-02 | The Regents Of The University Of California | Procede, compositions et dispositifs pour l'administration de polynucleotides nus qui codent des peptides a activite biologique |
WO1995006407A1 (fr) | 1993-08-30 | 1995-03-09 | The Regents Of The University Of California | Nouveau composant amyloide lie a la maladie d'alzheimer et procedes d'utilisation |
WO1995007301A1 (fr) | 1993-09-07 | 1995-03-16 | Smithkline Beecham Corporation | Anticorps recombines contre l'il4 utiles dans le traitement des affections induites par l'il4 |
US5652334A (en) | 1993-09-08 | 1997-07-29 | City Of Hope | Method for design of substances that enhance memory and improve the quality of life |
US5385887A (en) | 1993-09-10 | 1995-01-31 | Genetics Institute, Inc. | Formulations for delivery of osteogenic proteins |
WO1995007707A1 (fr) | 1993-09-14 | 1995-03-23 | Cytel Corporation | Alteration de la reponse immunitaire a l'aide de peptides se liant a des alleles pan dr |
US5736142A (en) | 1993-09-14 | 1998-04-07 | Cytel Corporation | Alteration of immune response using pan DR-binding peptides |
WO1995008999A1 (fr) | 1993-09-29 | 1995-04-06 | City Of Hope | TRAITEMENT DE L'AMNESIE DUE AU DEPOT DE LA PROTEINE AMYLOIDE β DANS LA MALADIE D'ALZHEIMER |
US5470951A (en) | 1993-09-29 | 1995-11-28 | City Of Hope | Peptides for antagonizing the effects of amyloid βprotein |
US5858981A (en) | 1993-09-30 | 1999-01-12 | University Of Pennsylvania | Method of inhibiting phagocytosis |
WO1995011311A1 (fr) | 1993-10-20 | 1995-04-27 | Duke University | PROCEDE DE LIAISON D'UN ELEMENT AU PEPTIDE β-AMYLOÏDE |
WO1995011008A2 (fr) | 1993-10-22 | 1995-04-27 | Genentech, Inc. | Procedes et compositions de microencapsulation d'adjuvants |
JPH07165799A (ja) | 1993-10-22 | 1995-06-27 | Tomoyasu Ra | 抗ヒト高親和性IgE受容体モノクローナル抗体に係るアミノ酸配列を有するポリペプチド、及びこれをコードするDNA断片 |
US5612486A (en) | 1993-10-27 | 1997-03-18 | Athena Neurosciences, Inc. | Transgenic animals harboring APP allele having swedish mutation |
WO1995011994A1 (fr) | 1993-10-27 | 1995-05-04 | Athena Neurosciences, Inc. | Procede de detection d'inhibiteurs de la production de peptides beta-amyloides |
US5744368A (en) | 1993-11-04 | 1998-04-28 | Research Foundation Of State University Of New York | Methods for the detection of soluble amyloid β-protein (βAP) or soluble transthyretin (TTR) |
WO1995012815A1 (fr) | 1993-11-04 | 1995-05-11 | The Research Foundation Of State University Of New York | PROCEDE EMPECHANT L'AGGLUTINATION DES PROTEINES β AMYLOIDES |
JPH07132033A (ja) | 1993-11-12 | 1995-05-23 | Hoechst Japan Ltd | アルツハイマー病モデルトランスジェニック動物 |
WO1995017085A1 (fr) | 1993-12-20 | 1995-06-29 | Genzyme Transgenics Corporation | Production transgenique d'anticorps dans le lait |
EP0868918A2 (fr) | 1993-12-23 | 1998-10-07 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | Vaccins |
US5434170A (en) | 1993-12-23 | 1995-07-18 | Andrulis Pharmaceuticals Corp. | Method for treating neurocognitive disorders |
US6262335B1 (en) | 1994-01-27 | 2001-07-17 | Johns Hopkins University | Transgenic mice expressing APP mutant at amino acids 717, 721 and 722 |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
US5935927A (en) | 1994-02-03 | 1999-08-10 | The Picower Institute For Medical Research | Compositions and methods for stimulating amyloid removal in amyloidogenic diseases using advanced glycosylation endproducts |
WO1995023166A1 (fr) | 1994-02-25 | 1995-08-31 | Deakin Research Limited | Epitopes de lymphocytes t inverses ou retro-inverses synthetiques |
WO1995023860A2 (fr) | 1994-03-04 | 1995-09-08 | Genentech, Inc. | PROTEINES INHIBITRICES PROPRES AU DOMAINE DE KÜNITZ DERIVEES DE L'INHIBITEUR DU PRECURSEUR DE LA β-PROTEINE AMYLOIDE DE LA MALADIE D'ALZHEIMER |
EP0758901B1 (fr) | 1994-04-21 | 2001-12-19 | Genetics Institute, Inc. | Preparations contenant il-11 |
US6270757B1 (en) | 1994-04-21 | 2001-08-07 | Genetics Institute, Inc. | Formulations for IL-11 |
US6372716B1 (en) | 1994-04-26 | 2002-04-16 | Genetics Institute, Inc. | Formulations for factor IX |
EP0758248B1 (fr) | 1994-04-26 | 2003-07-02 | Genetics Institute, LLC | Formulations s'appliquant au facteur ix |
WO1995031996A1 (fr) | 1994-05-25 | 1995-11-30 | Milkhaus Lab | Compositions et procedes de traitement de maladies a formation de plaque |
US5622701A (en) | 1994-06-14 | 1997-04-22 | Protein Design Labs, Inc. | Cross-reacting monoclonal antibodies specific for E- and P-selectin |
WO1996001126A1 (fr) | 1994-07-06 | 1996-01-18 | Immunomedics, Inc. | Vaccin multietape stimulant les reactions immunitaires en cascade |
US6417178B1 (en) | 1994-07-19 | 2002-07-09 | University Of Pittsburgh | Amyloid binding nitrogen-linked compounds for the antemortem diagnosis of alzheimer's disease, in vivo imaging and prevention of amyloid deposits |
WO1996003144A1 (fr) | 1994-07-27 | 1996-02-08 | The Council Of The Queensland Institute Of Medical Research | Vaccins a base de polyepitopes |
WO1996008665A1 (fr) | 1994-09-12 | 1996-03-21 | Ina Wälzlager Schaeffler Kg | Element de transmission pour commande de changement de vitesses |
WO1996014061A1 (fr) | 1994-11-03 | 1996-05-17 | Cell Genesys, Inc. | Nouveaux vecteurs adenoviraux, lignees cellulaires d'encapsidation, adenovirus recombines et procedes |
US6114133A (en) | 1994-11-14 | 2000-09-05 | Elan Pharmaceuticals, Inc. | Methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-β peptide (x-≧41) |
US5589154A (en) | 1994-11-22 | 1996-12-31 | Rutgers, The State University Of New Jersey | Methods for the prevention or treatment of vascular hemorrhaging and Alzheimer's disease |
WO1996015799A1 (fr) | 1994-11-22 | 1996-05-30 | Rutgers, The State University Of New Jersey | Methodes de prevention ou de traitement des hemorragies vasculaires et de la maladie d'alzheimer |
WO1996018900A1 (fr) | 1994-12-16 | 1996-06-20 | Ramot-Univ. Authority For Applied Research And Industrial Development Ltd. | Prevention de l'agregation des proteines |
US5688651A (en) | 1994-12-16 | 1997-11-18 | Ramot University Authority For Applied Research And Development Ltd. | Prevention of protein aggregation |
WO1996022373A3 (fr) | 1995-01-17 | 1996-10-03 | Univ Kentucky | Anticorps monoclonal 1a7 et son utilisation pour le traitement des melanomes et des carcinomes des petites cellules |
US5744132A (en) | 1995-02-06 | 1998-04-28 | Genetics Institute, Inc. | Formulations for IL-12 |
EP1842859B1 (fr) | 1995-02-14 | 2013-01-09 | Wyeth LLC | Anticorps monoclone spécifique de peptide A4 beta |
US5786180A (en) | 1995-02-14 | 1998-07-28 | Bayer Corporation | Monoclonal antibody 369.2B specific for β A4 peptide |
EP1160256B2 (fr) | 1995-02-14 | 2011-11-09 | Wyeth LLC | Anticorps monoclonal spécifique du peptide beta-A4 (1-42) |
WO1996025435A1 (fr) | 1995-02-14 | 1996-08-22 | Bayer Corporation | ANTICORPS MONOCLONAL SPECIFIQUE DU PEPTIDE βA4 |
US5624937A (en) | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
WO1996028471A1 (fr) | 1995-03-14 | 1996-09-19 | Praecis Pharmaceuticals Incorporated | Modulateurs de l'agregation de substances amyloides |
US5854215A (en) | 1995-03-14 | 1998-12-29 | Praecis Pharmaceuticals Incorporated | Modulators of β-amyloid peptide aggregation |
US5854204A (en) | 1995-03-14 | 1998-12-29 | Praecis Pharmaceuticals, Inc. | Aβ peptides that modulate β-amyloid aggregation |
US6303567B1 (en) | 1995-03-14 | 2001-10-16 | Praecis Pharmaceuticals, Inc . | Modulators of β-amyloid peptide aggregation comprising D-amino acids |
US5817626A (en) | 1995-03-14 | 1998-10-06 | Praecis Pharmaceuticals Incorporated | Modulators of beta-amyloid peptide aggregation |
WO1996029421A1 (fr) | 1995-03-23 | 1996-09-26 | Cantab Pharmaceuticals Research Limited | Vecteurs d'apport de genes |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US6121022A (en) | 1995-04-14 | 2000-09-19 | Genentech, Inc. | Altered polypeptides with increased half-life |
WO1996033739A1 (fr) | 1995-04-25 | 1996-10-31 | Smithkline Beecham Biologicals S.A. | Vaccins contenant une saponine ainsi qu'un sterol |
WO1996037621A2 (fr) | 1995-05-23 | 1996-11-28 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Proteines multimeres |
WO1996039176A1 (fr) | 1995-06-05 | 1996-12-12 | Brigham & Women's Hospital | Utilisation de la tolerance orale pour supprimer les reponses immunitaires de th1 et de th2 et pour supprimer la production d'anticorps |
WO1996040895A1 (fr) | 1995-06-07 | 1996-12-19 | Athena Neurosciences, Inc. | Procede d'identification de therapies de la maladie d'alzheimer a l'aide de modeles animaux transgeniques |
WO1996039834A1 (fr) | 1995-06-07 | 1996-12-19 | New York University | Peptides et compositions pharmaceutiques a base de tels peptides, destinees au traitement de troubles ou d'affections associees a un pliage anormal de proteine dans des depots amyloides ou de type amyloide |
US5910427A (en) | 1995-06-22 | 1999-06-08 | La Jolla Institute For Allergy And Immunology | Antigen non-specific glycosylation inhibiting factor derivatives |
US5989566A (en) | 1995-06-30 | 1999-11-23 | American Cyanamid Company | Stable vaccine compositions for parenteral administration, a method for their use, and a process for their preparation |
WO1997003192A3 (fr) | 1995-07-07 | 1997-04-03 | Darwin Molecular Corp | Gene du chromosome 1 et produits genetiques lies a la maladie d'alzheimer |
US20030202972A1 (en) | 1995-07-27 | 2003-10-30 | Genentech, Inc. | Protein formulation |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
WO1997005164A1 (fr) | 1995-07-27 | 1997-02-13 | Csl Limited | Produits de recombinaison de polyproteine de papillomavirus |
WO1997008320A1 (fr) | 1995-08-18 | 1997-03-06 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Banques de proteines/(poly)peptides |
US5824322A (en) | 1995-08-21 | 1998-10-20 | Cytrx Corporation | Compositions and methods for growth promotion |
US5846533A (en) | 1995-09-14 | 1998-12-08 | The Regents Of The University Of California | Antibodies specific for native PrPSc |
US6562341B2 (en) | 1995-09-14 | 2003-05-13 | The Regents Of The University Of California | Antibodies specific for native PrPSc |
WO1997010505A1 (fr) | 1995-09-14 | 1997-03-20 | The Regents Of The University Of California | ANTICORPS SPECIFIQUE DU PrPSc NATIF |
US5731284A (en) | 1995-09-28 | 1998-03-24 | Amgen Inc. | Method for treating Alzheimer's disease using glial line-derived neurotrophic factor (GDNF) protein product |
WO1997013855A1 (fr) | 1995-10-10 | 1997-04-17 | Novartis Ag | Proteine associee a un melanome |
US5985242A (en) | 1995-10-27 | 1999-11-16 | Praecis Pharmaceuticals, Inc. | Modulators of β-amyloid peptide aggregation comprising D-amino acids |
US5750361A (en) | 1995-11-02 | 1998-05-12 | The Regents Of The University Of California | Formation and use of prion protein (PRP) complexes |
WO1997017613A1 (fr) | 1995-11-10 | 1997-05-15 | Elan Corporation, Plc | Peptides favorisant le transport dans les tissus et procedes d'identification et d'utilisation correspondants |
WO1997018855A1 (fr) | 1995-11-21 | 1997-05-29 | Eduard Naumovich Lerner | Dispositif pour ameliorer l'administration a l'organisme de substances et de composes biologiquement actifs |
WO1997021728A1 (fr) | 1995-12-12 | 1997-06-19 | Karolinska Innovations Ab | PEPTIDE FIXANT LA SEQUENCE KLVFF DE L'AMYLOIDE $g(b) |
US6331440B1 (en) | 1995-12-12 | 2001-12-18 | Karolinska Innovations Ab | Peptide binding the KLVFF-sequence of amyloid-β |
EP0783104A1 (fr) | 1995-12-27 | 1997-07-09 | Oriental Yeast Co., Ltd. | Procédé de dosage du précurseur de l'amyloide |
US6015662A (en) | 1996-01-23 | 2000-01-18 | Abbott Laboratories | Reagents for use as calibrators and controls |
US5895654A (en) | 1996-01-25 | 1999-04-20 | Provost Fellows & Scholars Of The College Of The Univ. Of The Holy Undivided Trinity Of Queen Elisabeth | Streptococcus equi vaccine |
US5770700A (en) | 1996-01-25 | 1998-06-23 | Genetics Institute, Inc. | Liquid factor IX formulations |
WO1997026913A1 (fr) | 1996-01-26 | 1997-07-31 | The Trustees Of Columbia University In The City Of New York | POLYPEPTIDE PROVENANT D'UN EXTRAIT DE POUMON ET SE FIXANT A UN PEPTIDE AMYLOÏDE-$g(b) |
JPH09208485A (ja) | 1996-01-31 | 1997-08-12 | Teijin Ltd | ペプチド・蛋白質性薬物の水難溶性組成物 |
WO1997028816A1 (fr) | 1996-02-09 | 1997-08-14 | Ludwig Institute For Cancer Research | Compositions contenant des molecules immunogenes et facteur de stimulation de colonie de granulocytes-macrophages en tant qu'adjuvant |
WO1997032017A1 (fr) | 1996-02-26 | 1997-09-04 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Nouvelle methode pour l'identification de sequences d'acides nucleiques codant pour deux (poly)peptides interactifs, ou plus |
US6150091A (en) | 1996-03-06 | 2000-11-21 | Baylor College Of Medicine | Direct molecular diagnosis of Friedreich ataxia |
EP0845270A1 (fr) | 1996-03-23 | 1998-06-03 | The Research Foundation For Microbial Diseases Of Osaka University | Antigene a fragment fonctionnel de la toxine du tetanos, et vaccin contre le tetanos |
WO1997037031A1 (fr) | 1996-03-29 | 1997-10-09 | University Of Otago | Vecteurs de parapoxvirus |
WO1997036601A1 (fr) | 1996-04-03 | 1997-10-09 | Anergen, Inc. | Vaccins a peptides cycliques destines au traitement et a la prevention du diabete |
WO1997040147A1 (fr) | 1996-04-19 | 1997-10-30 | The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services | Regions reactives aux antigenes de la polyproteine du virus de l'hepatite a |
US6284533B1 (en) | 1996-05-01 | 2001-09-04 | Avant Immunotherapeutics, Inc. | Plasmid-based vaccine for treating atherosclerosis |
WO1998002462A1 (fr) | 1996-07-16 | 1998-01-22 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Domaines de la superfamille des immunoglobulines et fragments presentant une solubilite accrue |
WO1998004720A1 (fr) | 1996-07-26 | 1998-02-05 | Sloan-Kettering Institute For Cancer Research | Procedes et reactifs destines a l'immunisation genetique |
WO1998005350A1 (fr) | 1996-08-08 | 1998-02-12 | Milkhaus Laboratory, Inc. | Materiaux et procedes de traitement de maladies en plaques |
US7147851B1 (en) | 1996-08-15 | 2006-12-12 | Millennium Pharmaceuticals, Inc. | Humanized immunoglobulin reactive with α4β7 integrin |
WO1998007850A2 (fr) | 1996-08-22 | 1998-02-26 | Bergmann Johanna E | Agents pour la detection pre-symptomatique et le ciblage therapeutique de la maladie d'alzheimer et du syndrome de down chez l'homme |
WO1998008098A3 (fr) | 1996-08-22 | 1998-04-30 | Christian Fledelius | Detection d'acides amines-d dans les fluides corporels |
WO1998008868A1 (fr) | 1996-08-27 | 1998-03-05 | Praecis Pharmaceuticals Incorporated | Modulateurs de l'agregation de peptides beta-amyloides, comprenant des d-aminoacides |
US6057367A (en) | 1996-08-30 | 2000-05-02 | Duke University | Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses |
US20010021769A1 (en) | 1996-11-05 | 2001-09-13 | Prusiner Stanley B. | Somatic cells with ablated PrP gene and methods of use |
US6022859A (en) | 1996-11-15 | 2000-02-08 | Wisconsin Alumni Research Foundation | Inhibitors of β-amyloid toxicity |
WO1998022120A1 (fr) | 1996-11-19 | 1998-05-28 | The Wistar Institute Of Anatomy & Biology | Reactifs pour traiter et diagnostiquer la maladie d'alzheimer |
US6962984B2 (en) | 1996-12-05 | 2005-11-08 | Nihon University | IgA nephropathy-related DNA |
US20030207828A1 (en) | 1996-12-05 | 2003-11-06 | Tetsuyoshi Ishiwata | IgA nephropathy-related DNA |
US20030068316A1 (en) | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
WO1998033815A1 (fr) | 1997-02-05 | 1998-08-06 | Northwestern University | PROTEINE AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
US6218506B1 (en) | 1997-02-05 | 2001-04-17 | Northwestern University | Amyloid β protein (globular assembly and uses thereof) |
WO1998039303A1 (fr) | 1997-03-03 | 1998-09-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Petites molecules convenant au traitement d'une maladie inflammatoire |
US6277375B1 (en) | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
US5798102A (en) | 1997-03-04 | 1998-08-25 | Milkhaus Laboratory, Inc. | Treatment of cardiomyopathy |
US6057098A (en) | 1997-04-04 | 2000-05-02 | Biosite Diagnostics, Inc. | Polyvalent display libraries |
WO1998044955A1 (fr) | 1997-04-09 | 1998-10-15 | Mindset Ltd. | Anticorps recombines specifiques contre les terminaisons beta-amyloide, codage par molecule d'adn, et leurs procedes d'utilisation |
US20020086847A1 (en) | 1997-04-09 | 2002-07-04 | Mindset Biopharmaceuticals (Usa) | Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof |
US20030073655A1 (en) | 1997-04-09 | 2003-04-17 | Chain Daniel G. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
WO1998046642A1 (fr) | 1997-04-15 | 1998-10-22 | Farmaceutisk Laboratorium Ferring A/S | MOLECULES TNFα MODIFIEES, ADN CODANT POUR CES MOLECULES ET VACCINS COMPRENANT CES MOLECULES TNFα MODIFIEES ET CET ADN |
US20020058267A1 (en) | 1997-04-16 | 2002-05-16 | American Home Products Corporation | Beta-amyloid peptide-binding proteins and polynucleotides encoding the same |
US6339068B1 (en) | 1997-05-20 | 2002-01-15 | University Of Iowa Research Foundation | Vectors and methods for immunization or therapeutic protocols |
WO1998056418A1 (fr) | 1997-06-13 | 1998-12-17 | Genentech, Inc. | Formulation stabilisee renfermant un anticorps |
WO1999000150A2 (fr) | 1997-06-27 | 1999-01-07 | Regents Of The University Of California | Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline |
WO1999006066A2 (fr) | 1997-07-30 | 1999-02-11 | Abiogen Pharma S.P.A. | Anticorps monoclonaux catalytiques a activite protease permettant la lyse selective de la fraction proteinique des plaques et agregats lies a certaines pathologies |
WO1999006587A2 (fr) | 1997-08-01 | 1999-02-11 | Morphosys Ag | Nouvelle methode et nouveau phage d'identification d'une sequence d'acide nucleique |
WO1999006545A2 (fr) | 1997-08-01 | 1999-02-11 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Composition et nouveau procede pour depister les maladies dues a la formation d'agregats de proteines ou de fibrilles du type amyloide |
WO1999010008A1 (fr) | 1997-08-29 | 1999-03-04 | Aquila Biopharmaceuticals, Inc. | Compositions renfermant l'adjuvant qs-21 et du polysorbate ou de la cyclodextrine comme excipient |
US6175057B1 (en) | 1997-10-08 | 2001-01-16 | The Regents Of The University Of California | Transgenic mouse model of alzheimer's disease and cerebral amyloid angiopathy |
EP0921189B1 (fr) | 1997-11-14 | 2005-01-12 | Sankyo Company Limited | Animal transgénique comme modèle d'allergie et méthodes d'utilisation |
US20050163788A1 (en) | 1997-12-02 | 2005-07-28 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050196399A1 (en) | 1997-12-02 | 2005-09-08 | Schenk Dale B. | Prevention and treatment of amyloidogenic disease |
US20040081657A1 (en) | 1997-12-02 | 2004-04-29 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6750324B1 (en) | 1997-12-02 | 2004-06-15 | Neuralab Limited | Humanized and chimeric N-terminal amyloid beta-antibodies |
US20080096818A1 (en) | 1997-12-02 | 2008-04-24 | Elan Pharma International Limited | Prevention and treatment of amyloidogenic disease |
US20080227719A1 (en) | 1997-12-02 | 2008-09-18 | Elan Pharma International Limited | Prevention and treatment of amyloidogenic disease |
US20090069544A1 (en) | 1997-12-02 | 2009-03-12 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US20040171816A1 (en) | 1997-12-02 | 2004-09-02 | Schenk Dale B. | Humanized antibodies that recognize beta amyloid peptide |
US20040171815A1 (en) | 1997-12-02 | 2004-09-02 | Schenk Dale B. | Humanized antibodies that recognize beta amyloid peptide |
EP1690547A1 (fr) | 1997-12-02 | 2006-08-16 | Neuralab Limited | Prévention et traitement de maladie amyloidogène |
US7014855B2 (en) | 1997-12-02 | 2006-03-21 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
EP1690547B1 (fr) | 1997-12-02 | 2009-07-08 | Elan Pharma International Limited | Prévention et traitement de maladie amyloidogène |
US20060034858A1 (en) | 1997-12-02 | 2006-02-16 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20060029611A1 (en) | 1997-12-02 | 2006-02-09 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6787138B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6982084B2 (en) | 1997-12-02 | 2006-01-03 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20090297511A1 (en) | 1997-12-02 | 2009-12-03 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6972127B2 (en) | 1997-12-02 | 2005-12-06 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6710226B1 (en) | 1997-12-02 | 2004-03-23 | Neuralab Limited | Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics |
US6787140B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050255122A1 (en) | 1997-12-02 | 2005-11-17 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050249727A1 (en) | 1997-12-02 | 2005-11-10 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050249725A1 (en) | 1997-12-02 | 2005-11-10 | Schenk Dale B | Humanized antibodies that recognize beta amyloid peptide |
US6787523B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US7893214B2 (en) | 1997-12-02 | 2011-02-22 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
US6962707B2 (en) | 1997-12-02 | 2005-11-08 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6866850B2 (en) | 1997-12-02 | 2005-03-15 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6946135B2 (en) | 1997-12-02 | 2005-09-20 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050048049A1 (en) | 1997-12-02 | 2005-03-03 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050191314A1 (en) | 1997-12-02 | 2005-09-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050191292A1 (en) | 1997-12-02 | 2005-09-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6787144B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20130058869A1 (en) | 1997-12-02 | 2013-03-07 | Janssen Alzheimer Immunotherapy | Prevention And Treatment Of Amyloidogenic Disease |
US6923964B1 (en) | 1997-12-02 | 2005-08-02 | Neuralab Limited | Active immunization of AScr for prion disorders |
US6787143B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6913745B1 (en) | 1997-12-02 | 2005-07-05 | Neuralab Limited | Passive immunization of Alzheimer's disease |
US20050142132A1 (en) | 1997-12-02 | 2005-06-30 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6787139B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6808712B2 (en) | 1997-12-02 | 2004-10-26 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6905686B1 (en) | 1997-12-02 | 2005-06-14 | Neuralab Limited | Active immunization for treatment of alzheimer's disease |
US6743427B1 (en) | 1997-12-02 | 2004-06-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6890535B1 (en) | 1997-12-02 | 2005-05-10 | Neuralab Limited | Pharmaceutical compositions and methods for treatment of amyloid diseases |
WO1999027944A1 (fr) | 1997-12-02 | 1999-06-10 | Neuralab Limited | Prevention et traitement de maladie amyloidogene |
US6875434B1 (en) | 1997-12-02 | 2005-04-05 | Neuralab Limited | Methods of treatment of Alzheimer's disease |
US6866849B2 (en) | 1997-12-02 | 2005-03-15 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050019328A1 (en) | 1997-12-02 | 2005-01-27 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20040219146A1 (en) | 1997-12-02 | 2004-11-04 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6818218B2 (en) | 1997-12-02 | 2004-11-16 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20040265308A1 (en) | 1997-12-02 | 2004-12-30 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050013815A1 (en) | 1997-12-02 | 2005-01-20 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050019330A1 (en) | 1997-12-02 | 2005-01-27 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
WO1999027949A1 (fr) | 1997-12-03 | 1999-06-10 | Brigham And Women's Hospital | PROCEDES DE SUPPRESSION DES MODIFICATIONS LIEES AUX β-AMYLOIDES DANS LA MALADIE D'ALZHEIMER |
WO1999027911A1 (fr) | 1997-12-03 | 1999-06-10 | Fujisawa Pharmaceutical Co., Ltd. | Medicament en pastilles souples et procede de fabrication |
EP1033998B1 (fr) | 1997-12-03 | 2005-10-19 | Neuralab, Ltd. | Suppression des modifications liees aux beta-amyloides dans la maladie d'alzheimer |
GB2335192A (en) | 1998-02-23 | 1999-09-15 | Exonhit Therapeutics Sa | Models for neurodegenerative diseases |
US6538124B1 (en) | 1998-04-02 | 2003-03-25 | Genentech, Inc. | Polypeptide variants |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US7790856B2 (en) | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
US20070154480A1 (en) | 1998-04-07 | 2007-07-05 | Schenk Dale B | Humanized antibodies that recognize beta amyloid peptide |
US20050059802A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Ltd | Prevention and treatment of amyloidogenic disease |
US20050059591A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6936698B2 (en) | 1998-04-28 | 2005-08-30 | Smithkline Beecham | Monoclonal antibodies with reduced immunogenicity |
WO1999058564A1 (fr) | 1998-05-08 | 1999-11-18 | Norsk Hydro Asa | Mutants de dephasage de proteine de precurseur de beta-amyloide et d'ubiquitine-b et leur utilisation |
WO1999060021A2 (fr) | 1998-05-19 | 1999-11-25 | Yeda Research And Development Co. Ltd. | Lymphocytes t actives, antigenes specifiques du systeme nerveux et leur utilisation |
US20030147882A1 (en) | 1998-05-21 | 2003-08-07 | Alan Solomon | Methods for amyloid removal using anti-amyloid antibodies |
WO1999060024A1 (fr) | 1998-05-21 | 1999-11-25 | The University Of Tennessee Research Corporation | Procede d'elimination d'amyloide a l'aide d'anticorps anti-amyloide |
US6432710B1 (en) | 1998-05-22 | 2002-08-13 | Isolagen Technologies, Inc. | Compositions for regenerating tissue that has deteriorated, and methods for using such compositions |
US6727349B1 (en) | 1998-07-23 | 2004-04-27 | Millennium Pharmaceuticals, Inc. | Recombinant anti-CCR2 antibodies and methods of use therefor |
WO2000020027A2 (fr) | 1998-10-05 | 2000-04-13 | M & E Biotech A/S | Nouveaux procedes de vaccination therapeutique |
WO2000023082A1 (fr) | 1998-10-19 | 2000-04-27 | Yeda Research And Development Co. Ltd. | Traitement du lupus erythemateux systemique par regulation negative de la reponse auto-immune a des autoantigenes |
US7112661B1 (en) | 1998-10-30 | 2006-09-26 | The Research Foundation Of State University Of New York | Variable heavy chain and variable light chain regions of antibodies to human platelet glycoprotein Ib alpha |
WO2000026238A2 (fr) | 1998-11-04 | 2000-05-11 | D-Gen Limited | Materiaux biologiques et procedes utiles pour le diagnostic et le traitement de maladies |
US20050009150A1 (en) | 1998-11-30 | 2005-01-13 | Elan Pharmaceuticals, Inc. | Humanized antibodies that recognize beta amyloid peptide |
US7582733B2 (en) | 1998-11-30 | 2009-09-01 | Elan Pharma International Limited | Humanized antibodies that recognize beta amyloid peptide |
WO2000043049A1 (fr) | 1999-01-19 | 2000-07-27 | Pharmacia & Upjohn Company | Emballage a base de polyethylene sterilise par rayonnement gamma |
WO2000043039A1 (fr) | 1999-01-22 | 2000-07-27 | Matthew John During | Traitement de troubles psychologiques a base de vaccin |
US20070196375A1 (en) | 1999-02-24 | 2007-08-23 | Tact Ip, Llc | Methods to facilitate transmission of large molecules across the blood-brain, blood-eye, and blood-nerve barriers |
US20030054484A1 (en) | 1999-04-20 | 2003-03-20 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
WO2000068263A2 (fr) | 1999-05-05 | 2000-11-16 | Neurochem, Inc. | Peptides stereoselectifs antifibrillogenese et peptidomimetiques correspondants |
WO2000072880A2 (fr) | 1999-05-28 | 2000-12-07 | Neuralab Limited | Prevention et traitement de maladie amyloidogene |
US6787637B1 (en) | 1999-05-28 | 2004-09-07 | Neuralab Limited | N-Terminal amyloid-β antibodies |
EP1185298B1 (fr) | 1999-05-28 | 2009-06-24 | Elan Pharma International Limited | Prevention et traitement de maladie amyloidogene |
WO2000072870A1 (fr) | 1999-06-01 | 2000-12-07 | Neuralab, Ltd. | Compositions de peptide a-beta et leurs procedes de production |
WO2000072876A3 (fr) | 1999-06-01 | 2001-05-03 | Neuralab Ltd | Prevention et traitement de maladies amyloidogenes |
WO2000072876A2 (fr) | 1999-06-01 | 2000-12-07 | Neuralab Limited | Prevention et traitement de maladies amyloidogenes |
US20020136718A1 (en) | 1999-06-16 | 2002-09-26 | Boston Biomedical Research Institute | Immunological control of beta-amyloid levels in vivo |
WO2000077178A1 (fr) | 1999-06-16 | 2000-12-21 | Boston Biomedical Research Institute | Temoin immunologique de niveaux de $g(b)-amyloide <i/in vivo> |
US20050147613A1 (en) | 1999-06-16 | 2005-07-07 | Boston Biomedical Research Institute | Immunological control of beta-amyloid levels in vivo |
US20020102261A1 (en) | 1999-06-16 | 2002-08-01 | Boston Biomedical Research Institute | Immunological control of beta-amyloid levels in vivo |
US7906626B2 (en) | 1999-06-16 | 2011-03-15 | Boston Biomedical Research Institute | Immunological control of β-amyloid levels in vivo |
US6582945B1 (en) | 1999-06-16 | 2003-06-24 | Boston Biomedical Research Institute | Immunological control of β-amyloid levels in vivo |
US20060210964A1 (en) | 1999-07-01 | 2006-09-21 | Hyslop Paul A | Prevention and treatment of amyloid-associated disorders |
WO2001005355A2 (fr) | 1999-07-15 | 2001-01-25 | Genetics Institute, Inc. | Formulations d'il-11 |
WO2001010900A2 (fr) | 1999-08-04 | 2001-02-15 | University Of Southern California | PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
WO2001018169A3 (fr) | 1999-09-03 | 2001-11-22 | Univ Ramot | Agents et compositions et procedes utilisant lesdits agents et lesdites compositions pour le diagnostic et/ou le traitement ou la prevention des maladies formant des plaques. |
US20050152878A1 (en) | 1999-09-03 | 2005-07-14 | Ramot At Tel-Aviv University Ltd. | Agents and compositions and methods utilizing same useful in diagnosing and/or treating or preventing plaque forming diseases |
US20010018053A1 (en) | 1999-09-14 | 2001-08-30 | Mcmichael John | Methods for treating disease states comprising administration of low levels of antibodies |
US6294171B2 (en) | 1999-09-14 | 2001-09-25 | Milkhaus Laboratory, Inc. | Methods for treating disease states comprising administration of low levels of antibodies |
US6824780B1 (en) | 1999-10-29 | 2004-11-30 | Genentech, Inc. | Anti-tumor antibody compositions and methods of use |
US20020094335A1 (en) | 1999-11-29 | 2002-07-18 | Robert Chalifour | Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases |
WO2001039796A2 (fr) | 1999-11-29 | 2001-06-07 | Neurochem Inc. | Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides |
WO2001042306A2 (fr) | 1999-12-08 | 2001-06-14 | Mindset Biopharmaceuticals (Usa), Inc. | Peptides chimeriques comme immunogenes, anticorps contre ces immunogenes et techniques d'immunisation utilisant ces peptides chimeriques ou ces anticorps |
US6399314B1 (en) | 1999-12-29 | 2002-06-04 | American Cyanamid Company | Methods of detection of amyloidogenic proteins |
WO2001062284A2 (fr) | 2000-02-21 | 2001-08-30 | Pharmexa A/S | Nouvelle methode de regulation negative d'amyloide |
US20020187157A1 (en) | 2000-02-21 | 2002-12-12 | Jensen Martin Roland | Novel method for down-regulation of amyloid |
EP1481992A3 (fr) | 2000-02-24 | 2004-12-08 | Washington University St. Louis | Anticorps humanises sequestrant un peptide amyloide beta |
US7195761B2 (en) | 2000-02-24 | 2007-03-27 | Eli Lilly And Company | Humanized antibodies that sequester abeta peptide |
EP1481992A2 (fr) | 2000-02-24 | 2004-12-01 | Washington University St. Louis | Anticorps humanises sequestrant un peptide amyloide beta |
US20040043418A1 (en) | 2000-02-24 | 2004-03-04 | Holtzman David M. | Humanized antibodies that sequester Abeta peptide |
WO2001062801A2 (fr) | 2000-02-24 | 2001-08-30 | Washington University | Anticorps humanises sequestrant un peptide a$g(b) |
WO2001077167A2 (fr) | 2000-04-05 | 2001-10-18 | University Of Tennessee Research Corporation | Techniques d'etude, de diagnostic et de traitement d'amylose |
WO2001078777A2 (fr) | 2000-04-13 | 2001-10-25 | Mossman, Sally | COMPOSITIONS IMMUNOSTIMULANTES COMPRENANT UN PHOSPHATE D'AMINOALKYL GLUCOSAMINIDE ET DU QS-21 |
US20020077288A1 (en) | 2000-05-22 | 2002-06-20 | New York University | Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits |
WO2001090182A2 (fr) | 2000-05-22 | 2001-11-29 | New York University | Peptides immunogenes synthetiques mais non-amyloidogenes homologues de beta-amyloide, destines a induire une reaction immunitaire contre les peptides beta-amyloide et les depots amyloides |
US6713450B2 (en) | 2000-05-22 | 2004-03-30 | New York University | Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid β for induction of an immune response to amyloid β and amyloid deposits |
US20040247590A1 (en) | 2000-05-26 | 2004-12-09 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20040247591A1 (en) | 2000-05-26 | 2004-12-09 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050123544A1 (en) | 2000-05-26 | 2005-06-09 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20040265301A1 (en) | 2000-05-26 | 2004-12-30 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20050158304A1 (en) | 2000-05-26 | 2005-07-21 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6761888B1 (en) | 2000-05-26 | 2004-07-13 | Neuralab Limited | Passive immunization treatment of Alzheimer's disease |
US20060121038A9 (en) | 2000-05-26 | 2006-06-08 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US20020162129A1 (en) | 2000-07-07 | 2002-10-31 | Lars Lannfelt | Prevention and treatment of alzheimer's disease |
WO2002003911A2 (fr) | 2000-07-07 | 2002-01-17 | Lars Lannfelt | Prevention et traitement de la maladie d'alzheimer |
EP1172378A1 (fr) | 2000-07-12 | 2002-01-16 | Richard Dr. Dodel | Anticorps humains anti-beta-amyloid et leur utilisation pour le traitement de la maladie d'Alzheimer |
US20020009445A1 (en) | 2000-07-12 | 2002-01-24 | Yansheng Du | Human beta-amyloid antibody and use thereof for treatment of alzheimer's disease |
US20030092145A1 (en) | 2000-08-24 | 2003-05-15 | Vic Jira | Viral vaccine composition, process, and methods of use |
WO2002021141A2 (fr) | 2000-09-06 | 2002-03-14 | Aventis Pharma S.A. | Procedes et compositions relatifs a des maladies associees a l'amyloide |
WO2002034777A1 (fr) | 2000-10-24 | 2002-05-02 | Chiesi Farmaceutici S.P.A. | Proteines de fusion utilisees comme traitements d'immunisation contre la maladie d'alzheimer |
WO2002034878A2 (fr) | 2000-10-26 | 2002-05-02 | Yeda Research And Development Co. Ltd. | Proteine precurseur de l'amyloide (app) et peptides derives de l'app inhibant la croissance de tumeurs et de metastases |
US20030009104A1 (en) | 2000-11-02 | 2003-01-09 | Hyman Bradley T. | In vivo multiphoton diagnostic detection and imaging of a neurodegenerative disease |
US20020133001A1 (en) | 2000-11-27 | 2002-09-19 | Praecis Pharmaceuticals Inc. | Therapeutic agents and methods of use thereof for treating an amyloidogenic disease |
WO2002046237A3 (fr) | 2000-12-06 | 2003-09-04 | Neuralab Ltd | Anticorps humanises reconnaissant le peptide amyloide beta |
US20060280743A1 (en) | 2000-12-06 | 2006-12-14 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
US20040087777A1 (en) | 2000-12-06 | 2004-05-06 | Elan Pharmaceuticals, Inc. | Humanized antibodies that recognize beta amyloid peptide |
US20070238154A1 (en) | 2000-12-06 | 2007-10-11 | Elan Pharma International Limited | Humanized antibodies that recognize beta-amyloid peptide |
US7189819B2 (en) | 2000-12-06 | 2007-03-13 | Wyeth | Humanized antibodies that recognize beta amyloid peptide |
US20030165496A1 (en) | 2000-12-06 | 2003-09-04 | Elan Pharmaceuticals, Inc. | Humanized antibodies that recognize beta amyloid peptide |
US7179892B2 (en) | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
US20020132268A1 (en) | 2000-12-27 | 2002-09-19 | Jui-Yoa Chang | Prion isomers, methods of making, methods of using, and compositions and products comprising prion isomers |
US20020160394A1 (en) | 2001-01-24 | 2002-10-31 | Bayer Corporation | Regulation of transthyretin to treat obesity |
WO2002060481A1 (fr) | 2001-01-31 | 2002-08-08 | Milkhaus Laboratory, Inc. | Methodes de traitement d'etats pathologiques consistant a administrer des quantites faibles d'anticorps |
US20020168377A1 (en) | 2001-04-19 | 2002-11-14 | Hermann Schaetzl | Prion protein dimers useful for vaccination |
US20050090648A1 (en) | 2001-04-30 | 2005-04-28 | Naoya Tsurushita | Humanized antibodies |
WO2002088306A2 (fr) | 2001-04-30 | 2002-11-07 | Eli Lilly And Company | Anticorps humanises |
WO2002088307A2 (fr) | 2001-04-30 | 2002-11-07 | Eli Lilly And Company | Anticorps humanises |
US20040247612A1 (en) | 2001-05-25 | 2004-12-09 | Wang Chang Yi | Immunogenic peptide composition for the prevention and treatment of Alzheimer's Disease |
US20030068325A1 (en) | 2001-05-25 | 2003-04-10 | Wang Chang Yi | Immunogenic peptide composition for the prevention and treatment of Altzheimers Disease |
WO2002096937A2 (fr) | 2001-05-29 | 2002-12-05 | Neurochem, Inc. | Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees au substances amyloides |
WO2002096457A2 (fr) | 2001-05-31 | 2002-12-05 | Novartis Ag | Formulations liquides stable s |
US20020197258A1 (en) | 2001-06-22 | 2002-12-26 | Ghanbari Hossein A. | Compositions and methods for preventing protein aggregation in neurodegenerative diseases |
WO2003009817A2 (fr) | 2001-07-25 | 2003-02-06 | Protein Design Labs, Inc. | Formulation pharmaceutique lyophilisee stable d'anticorps igg |
US20030135035A1 (en) | 2001-08-09 | 2003-07-17 | Mark Shannon | Human ZZAP1 protein |
WO2003016467A3 (fr) | 2001-08-17 | 2004-01-15 | Lilly Co Eli | Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b) |
WO2003016467A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b) |
WO2003016466A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Anticorps anti-$g(a)$g(b) |
US20040241164A1 (en) | 2001-08-17 | 2004-12-02 | Bales Kelly Renee | Use of antibodies having high affinity for soluble ab to treat conditions and diseases related to ass |
WO2003015691A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Amelioration rapide des processus cognitifs dans les etats pathologiques lies a l'$g(a)$g(b) |
WO2003020212A2 (fr) | 2001-08-29 | 2003-03-13 | Mayo Foundation For Medical Education And Research | Traitement pour des troubles du systeme nerveux central |
US7625550B2 (en) | 2001-09-10 | 2009-12-01 | Anticancer, Inc. | Enhanced resolution of tumor metastasis using a skin flap model |
US20030166557A1 (en) | 2001-10-31 | 2003-09-04 | Board Of Regents, The University Of Texas System | SEMA3B inhibits tumor growth and induces apoptosis in cancer cells |
WO2003039485A2 (fr) | 2001-11-08 | 2003-05-15 | Protein Design Labs | Formulation pharmaceutique liquide stable d'anticorps igg |
US20030166558A1 (en) | 2001-11-21 | 2003-09-04 | New York University | Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid beta, prion protein, amylin, alpha-synuclein, or polyglutamine repeats for induction of an immune response thereto |
WO2003051374A2 (fr) | 2001-12-17 | 2003-06-26 | New York State Office Of Mental Health | SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE |
EP1321166B1 (fr) | 2001-12-21 | 2006-07-05 | Ethicon Inc. | Electrode de retour de masse déployable et méthode d'utilisation |
US20050169925A1 (en) | 2002-02-20 | 2005-08-04 | Michael Bardroff | Anti-amyloid beta antibodies and their use |
WO2003072036A3 (fr) | 2002-02-21 | 2003-12-31 | Univ Duke | Methodes therapeutiques utilisant des anticorps anti-cd22 |
WO2003072036A2 (fr) | 2002-02-21 | 2003-09-04 | Duke University | Methodes therapeutiques utilisant des anticorps anti-cd22 |
WO2003074081A1 (fr) | 2002-02-28 | 2003-09-12 | Mindset Biopharmaceuticals Usa Inc. | Anticorps specifiques contre un peptide $g(b)-amyloide, compositions pharmaceutiques et methodes d'utilisation |
US20040082762A1 (en) | 2002-03-12 | 2004-04-29 | Elan Pharmaceuticals, Inc. | Humanized antibodies that recognize beta amyloid peptide |
WO2003077858A3 (fr) | 2002-03-12 | 2005-05-19 | Neuralab Ltd | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
WO2003077858A2 (fr) | 2002-03-12 | 2003-09-25 | Neuralab Limited | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
US7256273B2 (en) | 2002-03-12 | 2007-08-14 | Elan Pharma International Limited | Humanized antibodies that recognize beta amyloid peptide |
WO2003104437A2 (fr) | 2002-06-11 | 2003-12-18 | Northwestern University | Anticorps anti-addl et leurs utilisations |
WO2003105894A1 (fr) | 2002-06-14 | 2003-12-24 | Medimmune, Inc. | Preparations d'anticorps anti-vrs liquides stabilisees |
EP1524994B1 (fr) | 2002-07-19 | 2011-04-27 | Cytos Biotechnology AG | Matrices d'antigenes amyloides beta1-6 |
WO2004016282A1 (fr) | 2002-07-19 | 2004-02-26 | Cytos Biotechnology Ag | Matrices d'antigenes amyloides $g(b)1-6 |
WO2004013172A3 (fr) | 2002-07-24 | 2004-04-08 | Innogenetics Nv | Prevention, traitement et diagnostic de maladies associees a la formation et/ou a l'agregation de la beta-amyloide |
WO2004013172A2 (fr) | 2002-07-24 | 2004-02-12 | Innogenetics N.V. | Prevention, traitement et diagnostic de maladies associees a la formation et/ou a l'agregation de la beta-amyloide |
WO2004031400A2 (fr) | 2002-10-01 | 2004-04-15 | Northwestern University | Ligands diffusibles derives de l'amyloide beta (addl), substituts d'addl, molecules de liaison aux addl, et leurs utilisations |
WO2004044204A2 (fr) | 2002-11-06 | 2004-05-27 | Institut Pasteur | Fragments variables d'anticorps de camelides a chaine unique et leurs applications pour le diagnostic et le traitement de pathologies diverses. |
WO2004044204A3 (fr) | 2002-11-06 | 2004-09-10 | Pasteur Institut | Fragments variables d'anticorps de camelides a chaine unique et leurs applications pour le diagnostic et le traitement de pathologies diverses. |
WO2004055164A2 (fr) | 2002-12-13 | 2004-07-01 | Abgenix, Inc. | Systeme et methode de stabilisation d'anticorps au moyen d'histidine |
US6787129B1 (en) | 2003-01-13 | 2004-09-07 | Zenitech Llc | Castor polyester as gloss agents in anionic systems |
WO2004069182A2 (fr) | 2003-02-01 | 2004-08-19 | Neuralab Limited | Immunisation active permettant de produire des anticorps contre a-beta soluble |
US20040213800A1 (en) | 2003-02-01 | 2004-10-28 | Seubert Peter A. | Active immunization to generate antibodies to soluble A-beta |
US20060188512A1 (en) | 2003-02-01 | 2006-08-24 | Ted Yednock | Active immunization to generate antibodies to solble a-beta |
WO2004071408A2 (fr) | 2003-02-10 | 2004-08-26 | Applied Molecular Evolution, Inc. | Molecules de liaison au peptide a$g(b) |
WO2004080419A2 (fr) | 2003-03-12 | 2004-09-23 | Neuralab Limited | Anticorps humanises reconnaissant le peptide beta-amyloide |
WO2004080419A3 (fr) | 2003-03-12 | 2005-05-06 | Neuralab Ltd | Anticorps humanises reconnaissant le peptide beta-amyloide |
US20040197324A1 (en) | 2003-04-04 | 2004-10-07 | Genentech, Inc. | High concentration antibody and protein formulations |
US20040265919A1 (en) | 2003-05-22 | 2004-12-30 | Hugo Vanderstichele | Method for the prediction, diagnosis and differential diagnosis of Alzheimer's disease |
US20050118651A1 (en) | 2003-05-30 | 2005-06-02 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
WO2004108895A3 (fr) | 2003-05-30 | 2005-07-28 | Neuralab Ltd | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
US7871615B2 (en) | 2003-05-30 | 2011-01-18 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
WO2004108895A2 (fr) | 2003-05-30 | 2004-12-16 | Neuralab Limited | Anticorps humanises qui reconnaissent le peptide beta-amyloide |
US20060182321A1 (en) | 2003-07-07 | 2006-08-17 | Agency For Science, Technology And Research | Method and apparatus for extracting third ventricle information |
WO2005014041A2 (fr) | 2003-07-24 | 2005-02-17 | Novartis Ag | Substances et procedes pour le traitement des amyloses |
WO2005026211A2 (fr) | 2003-09-05 | 2005-03-24 | Eli Lilly And Company | Anticorps anti-ghreline |
WO2005026211A3 (fr) | 2003-09-05 | 2005-06-16 | Lilly Co Eli | Anticorps anti-ghreline |
US20060234912A1 (en) | 2003-10-08 | 2006-10-19 | Wang Yu T | Methods for modulating neuronal responses |
WO2005035753A1 (fr) | 2003-10-10 | 2005-04-21 | Chugai Seiyaku Kabushiki Kaisha | Anticorps a double specificite remplaçant une proteine fonctionnelle |
US20070134762A1 (en) | 2003-12-17 | 2007-06-14 | Arumugham Rasappa G | Immunogenic peptide carrier conjugates and methods of producing same |
US20080145373A1 (en) | 2003-12-17 | 2008-06-19 | Elan Pharmaceuticals, Inc. | A-beta immunogenic peptide carrier conjugates and methods of producing same |
WO2005058941A2 (fr) | 2003-12-17 | 2005-06-30 | Elan Pharmaceuticals, Inc. | Conjugues porteurs de peptide immunogene a? les techniques de production de ces conjugues |
WO2005058940A2 (fr) | 2003-12-17 | 2005-06-30 | Wyeth | Conjugues porteurs de peptides immunogenes et procedes de production associes |
US20070161088A1 (en) | 2003-12-17 | 2007-07-12 | Elan Pharmaceuticals, Inc. | Beta immunogenic peptide carrier conjugates and methods of producing same |
US20050214222A1 (en) | 2004-02-13 | 2005-09-29 | Mckinnon Stuart J | In vivo imaging of amyloid plaques in glaucoma using intravenous injectable dyes |
WO2005090315A1 (fr) | 2004-03-15 | 2005-09-29 | Janssen Pharmaceutica, N. V. | Nouveaux composes en tant que modulateurs de recepteurs d'opioides |
US20080219931A1 (en) | 2004-07-02 | 2008-09-11 | University Of Pittsburgh | Amyloid Imaging as a Surrogate Marker for Efficacy of Anti-Amyloid Therapies |
US20060057701A1 (en) | 2004-07-30 | 2006-03-16 | Arnon Rosenthal | Antibodies directed against amyloid-beta peptide and methods using same |
WO2006031653A2 (fr) | 2004-09-10 | 2006-03-23 | Wyeth | Anticorps anti-5t4 humanises et conjugues anticorps anti-5t4/calicheamicine |
US20060099206A1 (en) | 2004-10-05 | 2006-05-11 | Sinacore Martin S | Methods and compositions for improving recombinant protein production |
WO2006042158A3 (fr) | 2004-10-05 | 2006-06-22 | Wyeth Corp | Procedes et compositions permettant d'ameliorer la production de proteines recombinees |
US20060160161A1 (en) | 2004-10-26 | 2006-07-20 | Elan Pharmaceuticals, Inc. | Methods for assessing antibodies to neurodegenerative disease-associated antigens |
US20060198851A1 (en) | 2004-12-15 | 2006-09-07 | Guriq Basi | Humanized Abeta antibodies for use in improving cognition |
WO2006066171A1 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Anticorps amyloide ???? utilises afin d'ameliorer la cognition |
US20060257396A1 (en) | 2004-12-15 | 2006-11-16 | Jacobsen Jack S | Abeta antibodies for use in improving cognition |
US20060240486A1 (en) | 2004-12-15 | 2006-10-26 | Johnson-Wood Kelly L | Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies |
WO2006066049A2 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Anticorps humanises reconnaissant le peptide beta amyloide |
US20060153772A1 (en) | 2004-12-15 | 2006-07-13 | Wyeth | Contextual fear conditioning for predicting immunotherapeutic efficacy |
US20060165682A1 (en) | 2004-12-15 | 2006-07-27 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US20060210557A1 (en) | 2005-01-28 | 2006-09-21 | Donna Luisi | Stabilized liquid polypeptide formulations |
WO2006083689A2 (fr) | 2005-01-28 | 2006-08-10 | Elan Pharma International Limited | Preparation d'anticorps anti-a$g(b) |
WO2006081587A3 (fr) | 2005-01-28 | 2006-10-12 | Wyeth Corp | Formulations polypeptidiques liquides stabilisees |
US20060193850A1 (en) | 2005-01-28 | 2006-08-31 | Warne Nicholas W | Anti a beta antibody formulation |
WO2006081587A2 (fr) | 2005-01-28 | 2006-08-03 | Wyeth | Formulations polypeptidiques liquides stabilisees |
WO2006121656A2 (fr) | 2005-05-05 | 2006-11-16 | Merck & Co., Inc. | Compositions a base de conjugues peptidiques et methodes destinees a la prevention et au traitement de la maladie d'alzheimer |
US20070082367A1 (en) | 2005-06-17 | 2007-04-12 | Ranganathan Godavarti | Methods of purifying anti a beta antibodies |
US20070072307A1 (en) | 2005-06-17 | 2007-03-29 | Ranganathan Godavarti | Methods of purifying Fc region containing proteins |
US20070021454A1 (en) | 2005-07-18 | 2007-01-25 | Coburn Craig A | Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease |
EP1950991B1 (fr) | 2005-10-04 | 2016-09-21 | Huawei Technologies Co., Ltd. | Dispositif de station mobile, système et procede pour le mappage de bande de frequences utilisée par le dispositif de station mobile |
US20080031954A1 (en) | 2005-11-10 | 2008-02-07 | Daniel Paris | Modulation of angiogenesis by a-beta peptide fragments |
US20110142824A1 (en) | 2006-03-30 | 2011-06-16 | Glaxo Group Limited | Antibodies Against Amyloid-Beta Peptide |
US20110229413A1 (en) | 2006-04-18 | 2011-09-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
WO2008011348A2 (fr) | 2006-07-14 | 2008-01-24 | Ac Immune S.A. | Anticorps humanisé |
WO2008114801A1 (fr) | 2007-03-12 | 2008-09-25 | National Institute Of Radiological Sciences | Visualisation par tomographie par émission de positons d'une neuro-inflammation associée aux amyloïdes dans le cerveau |
WO2008131298A3 (fr) | 2007-04-18 | 2008-12-18 | Elan Pharma Int Ltd | Prévention et traitement d'angiopathie amyloïde cérébrale |
WO2008131298A2 (fr) | 2007-04-18 | 2008-10-30 | Elan Pharma International Limited | Prévention et traitement d'angiopathie amyloïde cérébrale |
US20090142270A1 (en) | 2007-04-18 | 2009-06-04 | Elan Pharma International Limited | Prevention and treatment of cerebral amyloid angiopathy |
US20100221187A1 (en) | 2007-07-27 | 2010-09-02 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
WO2009017467A1 (fr) | 2007-07-27 | 2009-02-05 | Elan Pharma International Limited | Traitement de maladies amyloïdogéniques |
US20100266505A1 (en) | 2007-10-17 | 2010-10-21 | Wyeth Llc | Immunotherapy regimes dependent on apoe status |
US20090155256A1 (en) | 2007-10-17 | 2009-06-18 | Wyeth | Immunotherapy Regimes Dependent On APOE Status |
WO2009052439A2 (fr) | 2007-10-17 | 2009-04-23 | Elan Pharma International Limited | Régimes immunothérapeutiques dépendant du statut de l'apoe |
US20120070379A1 (en) | 2007-10-17 | 2012-03-22 | Janssen Alzheimer Immunotherapy | Immunotherapy regimes dependent on apoe status |
US7928203B2 (en) | 2007-12-28 | 2011-04-19 | Elan Pharmaceuticals, Inc. | Chimeric, humanized, or human antibody 2A4 |
WO2010033861A1 (fr) | 2008-09-18 | 2010-03-25 | Cedars-Sinai Medical Center | Procédé optique pour la détection de la maladie d'alzheimer |
WO2010044803A1 (fr) | 2008-10-17 | 2010-04-22 | Elan Pharma International Limited | Traitement de maladies amyloïdogènes |
WO2011106732A1 (fr) | 2010-02-25 | 2011-09-01 | Wyeth Llc | Surveillance pet d'une immunothérapie dirigée contre l'aβ |
WO2011133919A1 (fr) | 2010-04-22 | 2011-10-27 | Janssen Alzheimer Immunotherapy | Utilisation de tau pour un suivi d'immunothérapie |
Non-Patent Citations (1328)
Title |
---|
' Selkoe, Dennis J., "The Molecular pathology of Alzheimer's Disease," Neuron, 6:487-498 (1991). |
"AAB-001 in Patients with Mild to Moderate Alzheimer's Disease" ClinicalTrials.gov last updated Sep. 22, 2009 3 pages. |
"Madrid: News from the Vaccine Front," Aug. 1, 2008 (Aug. 1, 2008) pp. 1-7. |
"Researchers Develop Blood Test to Diagnose Alzheimer's- Type Changes in Mice," downloaded from www.businesswire.com on Dec. 15, 2004. |
Abcam, "Anti-beta Amyloid antibody 6F/3D", Nucleic Acids Res. 38:D142-D148 (2010). |
Abott, et al., "Transporting therapeutics across the blood-brain barrier" Molecular Medicine Today, pp. 106-113, Mar. 1996. |
Agadjanyan et al., "Prototype Alzheimer's Disease Vaccine Using the Immunodominant B Cell Epitope From {beta}-Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide," J. Immunol., 174:1580-1586 (2005). |
Aguzzi et al., "Prion research: the next frontiers," Nature, 389:795-798 (1997). |
Aihara, et al., "Immunocytochemical Localization of Immunoglobulins in the Rat Brain: Relationship to the Blood-Brain Barrier", J of Comparative Neurology 342:481-496 (1994). |
Aisen, P., "Inflammation and Alzheimer's Disease: Mechanisms and Therapeutic Strategies," Gerontology, 43:143-149 (1997). |
Akahori et al. Immunoglobulin kappa light chain VLJ region [Homo sapiens]. GenBank accession No. BAC01733. Jul. 2, 2002. * |
Akiyama et al., "Inflammation and Alzheimer's disease," Neurobiology of Aging, 21:383-421 (2000). |
Akiyama et al., "Occurrence of the Diffuse Amyloid beta-Protein (Abeta) Deposits With Numerous Abeta-Containing Glial Cells in the Cerebral Cortex of Patients With Alzheimer's Disease," Glia, 25:324-331 (1999). |
Akiyama et al., "Occurrence of the Diffuse Amyloid β-Protein (Aβ) Deposits With Numerous Aβ-Containing Glial Cells in the Cerebral Cortex of Patients With Alzheimer's Disease," Glia, 25:324-331 (1999). |
Akiyama et al., "The amino-terminally truncated forms of amyloid β-protein in brain macrophages in the ischemic lesions of Alzheimer's disease patients," Neuroscience Letters, 219:115-118 (1996). |
Alberts et al, Molecular Biology of the Cell, 2nd Edition, pp. 266-267, Garland Publishing Inc., New York (1989). |
Alberts et al., eds. Molecular Biology of the Cell, Third Edition, chapter 23, pp. 1208-1209 (1994). |
Alberts et al., eds. Molecular Biology of the Cell, Third Edition, chapter 23, pp. 1216-1218 (1994). |
Allen et al, "Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI Regimen for Metastatic Colon Caner," Arch. Neurol., 63(10): 1475-1478 (2006), abstract only. |
Alzheimer Research Forum, "Drugs in Clinical Trials" Oct. 18, 2010. |
American Type Culture Collection (ATCC) Search Results for "1KTR, 1 ETZ, 1JRH", http://www.atcc.org/, pp. 1-3, Feb. 22, 2007. |
Amit et al., "Three-Dimensional Structure of an Antigen-Antibody Complex at 2.8 Å Resolution," Science, 233:747-753 (1986). |
Andersen et al., "Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?", Neurology, 45:1441-1445 (1995). |
Anderson, J. P., "Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells," Neuroscience Letters, 128(1):126-128 (1991). |
Anderson, M. W., "Amending the amyloid hypothesis," The Scientist, 18(20):28-29 (2004). |
Andrew et al., Current Protocols in Immunology, 2.7.1-2.9.8, John Wiley & Sons, Inc. (1997). |
Andrews, et al., "Amino acid sequence of the variable regions of heavy chains from two idiotypically cross-reactive human IgM anti-gamma-globulins of the Wa group", Biochemistry, Sep. 29, 1981;20(20):5822-5830. |
Andrews, et al., "Complete amino acid sequence of variable domains from two monoclonal human anti-gamma globulins of the Wa cross-idiotypic group: Suggestion that the J segments are involved in the structural correlate of the idiotype", Proc. Natl. Acad. Sci. USA, vol. 78, No. 6, pp. 3799-3803, Jun. 1981. |
Ankarcrona et al., "Biomarkers for apoptosis in Alzheimer's disease," Int. J. Geriatric Psychiatry, 20:101-105 (2005). |
Annual Report of Johnson and Johnson p. 1-6 (2012). |
Applicants' submission in EP 07012421.9 dated Jun. 16, 2009. |
Aquila Press Release, PR Newswire. May 6, 1997. |
Ard et al., "Scavenging of Alzheimer's Amyloid β-Protein by Microglia in Culture," J. Neuroscience Research, 43:190-202 (1996). |
Arendiash et al., "Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: Task specificity and correlations between Abeta deposition and spatial memory," DNA and Cell Biology, 20(11):737-744(2001). |
Arendiash et al., "Behavioral assessment of Alzheimer's transgenic mice following long-term Aβ vaccination: Task specificity and correlations between Aβ deposition and spatial memory," DNA and Cell Biology, 20(11):737-744(2001). |
Armour et al., "Recombinant human IgG molecules lacking Fcγ receptor I binding and monocyte triggering activites," J. Immunol, 29:2613-2624 (1999). |
Arriagada, et al., "Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease", Neurology, 42:631-639 (1992). |
Askelof et al., "Protective immunogenicity of two synthetic peptides selected from the amino acid sequence of Bordetella pertussis toxin subunit S1," PNA, 87:1347-1351 (1990). |
Assignment executed Dec. 8, 2000 in respect of U.S. Appl. No. 60/067,740. |
Assignment executed Dec. 8, 2000 in respect of U.S. Appl. No. 60/080,970. |
Associated Press, "Immune cells may promote Alzehimer's, a study finds " The Boston Globe(Apr. 13, 1995). |
Auclair et al., "Effect of Active Immunization Against Oestriadiol in Developing Ram Lambs on Plasma Gonadotrophin and Testosterone Concentrations, Time of Onset of Puberty and Testicular Blood Flow," Journal of Reproduction and Fertility, 104:7-16. |
Auld et al., "Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies," Progress in Neurobiol., 68:209-245 (2002). |
Auld et al., "Alzheimer's disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies," Progress in Neurobiol., 68:209-245 (2002). |
Avis, "Perenteral Preparations," Remington's Pharmaceutical Sciences, 17:1518-1519 (1985). |
Aylward et al., "Cerebellar Volume in Adults With Down Syndrome," Arch Neurol., 4(2):209-212 (1997). Abstract only. |
Bach et al., "Vaccination with AB-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral AB and Lowers Plaque Burden in APP Transgenic Mice," J. Immunol., 2009, 182 7613-7624. |
Bacskai et al., "Imaging of amyloid-betadeposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy," Nature Medicine, 7(3):369-372 (2001). |
Bacskai et al., "Imaging of amyloid-βdeposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy," Nature Medicine, 7(3):369-372 (2001). |
Bacskai et al., "Non-Fc-mediated mechanisms are involved in clearance of amyloid-betain vivo by immunotherapy," J. Neurosci., 22(18):7873-7878 (2002). |
Bacskai et al., "Non-Fc-mediated mechanisms are involved in clearance of amyloid-βin vivo by immunotherapy," J. Neurosci., 22(18):7873-7878 (2002). |
Balbach et al., "Amyloid fibril formation by Abeta16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR," Biochemistry, 39:13748-13759. |
Balbach et al., "Amyloid fibril formation by Aβ16-22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR," Biochemistry, 39:13748-13759. |
Bales et al., "Administration of an Anti-Aβ Fab Fragment to APPV717F Transgenic Mice Reduces Neuritic Plague," Abstract P$-396, p. S587, presented at Poster Session P4: Therapeutics and Therapeutic Strategies-Therapeutic Strategies, Amyloid-Based. |
Bales et al., "Administration of an Anti-Aβ Fab Fragment to APPv717F Transgenic Mice Reduces Neuritic Plaque," Abstract P4-396, presented at Poster Session P4: Therapeutics and Therapeutic Strategies-Therapeutic Strategies, Amyloid-Based, Neurogiology of Aging, 25:S587 (2004). |
Bales et al., "Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Aβ antibody," J. Clin. Invest., 116(3):825-832 (2006). |
Bandlow et al., "Untersuchungen Zum Mechanismus Der Immunologischen Adjvanswirung des Vacciniavirus1,"Archiv für due gesamte Virusfoschung, 38:192-204.(1972). German article. |
Barbour, et al., Presentation of "Efficacy and Neuropathology of Passively Administered N-Terminal and Midregion Anti-Abeta Antibodies Alone and in Combination in the PDAPP Mouse" Elan Report pp:1-99 May 2007. |
Bard et al., "Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer's disease-like neuropathology," PNAS, 100(4):2023-2028 (2003). |
Bard et al., "Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology," PNAS, 100(4):2023-2028 (2003). |
Bard et al., "Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease," Nature Medicine, 6(8):916-919 (2000). |
Bard et al., "Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease," Nature Medicine, 6(8):916-919 (2000). |
Barelli et al., "Characterization of New Polyclonal Antibodies Specific for 40 and 42 Amino Acid-Long Amyloid β Peptides: Their Use to Examine the Cell Biology of Presenilins and the Immunohistochemistry of Sporadic Alzheimer's Disease and Cerebral Amyloid Angiopathy Cases," Molecular Medicine, 3(10):695-707 (1997). |
Barrow et al., "Solution Conformations and aggregational Properties of Synthetic Amyloid Beta-Peptides of Alzheimer's Disease. Analysis of Circular. Dichroism Spectra," J. Mol. Biol., 225(4):1075-1093 (1992). |
Bauer et al., "Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices," FEBS Letters, 285(1):111-114 (1991). |
Bauer et al., "Interleukin-6 and α-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices," FEBS Letters, 285(1):111-114 (1991). |
Beasley, "Alzheimer's traced to proteins caused by aging," Reuters, Apr. 20, 2001 7:56 PM ET. |
Begley, "Delivery of Therapeutic Agents to the Central Nervouse System: The Problems and the Possibilities," Pharmacol. Therapy, 104(1): 29-45 (Oct. 2004). |
Bellotti et al., "Application of Monoclonal Anti-idiotypes in the Study of AL Amyloidosi: Therapeutic Implications," Renal Failure, 15(3):365-371 (1993). |
Bending, "Humanization of Rodent Monoclonal Antibodies by CDR Grafting," A Companion to Methods in Enzymology, 8:83-93 (1995). |
Benjamini et al., from Immunology A Short Course, Second Edition, Chapter 4, Antibody Structure, pp. 49-65, 1991, published by Wiley-Liss, Inc., New York, New York. |
Benjamini et al., from Immunology A Short Course, Second Edition, pp. 136-138, 143, 73-74, 372-373, and 400-401, 1991, published by Wiley-Liss, Inc., New York, New York. |
Benkirane, et al, "Antigenicity and Immunogenicity of Modified Synthetic Peptides Containing -DAmino Acid Residues," J. Biol. Chem., 268(23):26279-26285 (1993). |
Ben-Yedidia et al., "Design of peptide and polypeptide vaccines," Current Opinion in.Biotechnology, 8:442-448 (1997). |
Bercovici et al., "Chronic Intravenous Injections of Antigen Induce and Maintain Tolerance in T Cell Receptor-Transgenic Mice " Eur. J. Immunol. 29:345-354 (1999). |
Bickel et al., "Development and in Vitro Characterization of a Cationized Monoclonal Antibody against betaA4 Protein: A Potential Probe for Alzheimer's Disease," Bioconjuate Chem., 5:119-125 (1994). |
Bickel et al., "Development and in Vitro Characterization of a Cationized Monoclonal Antibody against βA4 Protein: A Potential Probe for Alzheimer's Disease," Bioconjuate Chem., 5:119-125 (1994). |
Bickel et al., "Site Protected, Cationized Monoclonal Antibody Against Beta Amyloid as a Potential Diagnostic Imaging Technique for Alzheimer's Diseases," Soc. for Neuroscience Abstracts, 18:764 (1992). |
Biewenga et al., "Cleavage of Protein A-binding IgA1 with IgA1 Protease From Streptococcus Sanguls," Immunol Commun., 12(5):491-500 (1983), abstract only. |
Birmingham et al., "Set back to Alzheimer vaccine studies" Nature Medicine 8(3):199-200 (2002). |
Black et al., "A Single Ascending Dose Study of Bainezumab, A Humanized Monoclonal Antibody to Aβ , in AS," 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 1 p. (Apr. 20, 2006). Abstract only. |
Blasberg et al., "Regional Localization of Glioma-assoicated Antigen Defined by Monoclonal Antibody 81C6 in Vivo: Kinetics and Implications for Diagnosis and Therapy," Cancer Research, 47:4432-4443 (1987). |
Blass, "Immunologic Treatment of Alzheimer's Disease," New England J. Medicine, 341(22):1694 (1999). |
Bodmer et al., "Transforming Growth Factor-Beta Bound to Soluble Derivatives of the Beta Amyloid Precursor Protein of Alzheimer's Disease," Biochem. Biophys. Res. Comm., 171(2):890-897 (1990). |
Boraschi et al., "Interleukin-1 and Interleukin-1 Fragments a Vaccine Adjuvants", Methods, 1999, 19, pp. 108-113. |
Borchelt et al., "Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins," Neuron, 19:939-945 (1997). |
Borenstein, S., "New Alzheimer's vaccine to be tested on people soon, Early experiments on mice halted condition; considered safe for humans," Free Press, Jul. 23, 2001. |
Boris-Lawrie et al., "Recent advances in retrovirus vector technology," Cur. Opin. Genetic Develop., 3:102-109 (1993). |
Bork et al., "Go hunting in sequence databases but watch out for the traps," Trends in Genetics, 12(10):425-427 (1996). |
Bork, P., "Powers and Pitfalls in Sequence Analysis: The 70% Hurdle," Genome Research, 10:398-400 (2000). |
Borras-Cuesta et al., "Engineering of Immunogenic Peptides by Co-Linear Synthesis of Determinants Recognized by B and T Cells," Eur. J. Immunol., 17:1213-1215 (1987). |
Brazil et at., "Effects of Incorporation of Immunoglobulin G and Complement Component C1q on Uptake and Degradation of Alzheimer's Disease Amyloid Fibrils by Microglia," J. Biol. Chem., 275(22):16941-16947 (2000). |
Brenner, S. E., "Errors in genome annotation," Trends in Genetics, 15(4):132-133 (1999). |
Brice et al., "Absence of the amyloid precursor protein gene mutation (APP717 : Val->Ile) in 85 cases of early onset Alzheimer's disease," J. Neurology. Neurosurg. Psychiatry, 56:112-115 (1993). |
Brinkman, "Splice Variants as Cancer Biomarkers," Clinical Biochemisrty, 37(7):584-594 (2004). |
Britt et al., "Formulation of an immunogenic human cytomegalovirus vaccine: responses in mice," J. Infect. Dis., 171:18-25 Abstract (1995). |
Broadwell et al., "Serum proteins bypass the blood-brain fluid barriers for aextracelllar entry to the central nervous system," Exp. Neurol., 120(2):245-263 (1993). |
Brookmeyer et al., "Projections of Alzheimer's Disease in the United States and the Public Health Impact of Delaying Disease Onset," Am. J. Pubic Health, 881337-1342 (1998). |
Bruggermann, et al. "The Immunogenicity of Chimeric Antibodies" J. Exp Med., 170(2):153-2157 (1989). |
Burbach et al. "Vessel ultrastructure in APP23 transgenic mice after passive anti-Aβ immunotherapy and subsequent intracerebral hemorrhage" Neurobiology of Aging 28:202-212 (2007). |
Burdick et al., "Assembly and aggregartion properties of synthetic Alzheimer's A4/beta amyloid peptide antigens," J. Bid. Chem., 267:546-555 (1992). |
Burdick et al., "Assembly and aggregartion properties of synthetic Alzheimer's A4/β amyloid peptide antigens," J. Bid. Chem., 267:546-555 (1992). |
Bussiere et al., "Morphological Characterization of Thioflavin-S-Positive Amyloid Plaques in Transgenic Alzheimer Mice and Effect of Passive Aβ Immunotherapy on Their Clearance," Am. J. Pathology, 165(3):987-995 (2004). |
Buttini et al., "β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease," The Journal of Neuroscience, 25(40):9096-9101 (2005). |
Cameron, "Recent Advances in Transgenic Technology," Molecular Biotechnology, 7:253-265 (1997). |
Capra, et al., "Structure of Antibodies with Shared Idiotypy: The Complete Sequence of the Heavy Chain Variable Regions of Two Immunoglobulin M Anti-Gamma Globulins", Proc. Nat. Acad. Sci. USA, vol. 71, No. 10, pp. 4032-4036, Oct. 1974. |
Caputo et al., "Therapeutic approaches targeted at the amyloid proteins in Alzheimer's disease," Clin. Neuropharm., 15:414A-414B (1992). |
Casadesus et al., "The Estrogen Myth: Potential Use of Gonadotropin-Releasing Hormone Agonists for the Treatment of Alzheimer's Disease," Drugs R D, 7(3):187-193 (2006). |
Casey, S.O., "Posterior Reversible Encephalopathy Syndrome: Utility of Fluid-attenuated Inversion Recovery MR Imaging in the Detection of Cortical and Subcortical Lesions," Amer J Neuroradiol, 21:1199-1206 (2000). |
Cassell et al., "Demography and Epidemiology of Age-Associated Neuronal Impairment," chapter 4, pp. 31-50 from Funcitional Neurobiology of Aging, Hof et al., eds., Academic Press (2001). |
Casset et al., "A Peptide Mimetic of an Anti-CD4 Monoclonal Antibody by Rational Design," Biochemical and Biophysical Research Commiunications, 307:198-205 (2003). |
Castillo et al., "Amylin / Islet Amyloid Polypeptide: Biochemistry, Physiology, Patho-Physiology," Diabete & Metabolisme (Paris), 21:3-25 (1995). |
Castillo, "Poor results halt production, studies on promising Alzheimer's drug bapineuzumab" CBS Interactive Inc., Nov. 7, 2012 pp. 1/1. |
Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Thimerosal in Vaccines (Mercury in Plasma-Derived Products), web site contents found at : http://www.fda.gov/cber/vaccine/thimerosal.htm, last updated May 16, 2002. |
Centers for Disease Control and Prevention, "Vaccine Safety" Retrieved from www.cdc.gov/vaccinesafety/concerns/adjuants.html (Oct. 18, 2012) p. 1-2. |
Chakrabarti et al., "Vaccinia Virus Expression Vector: Coexpression of B-Galactosidas Provides Visual Screening of Recombinant Virus Plaques," Molecular and Cellular Biology, 5(12):3403-3409 (1985). |
Chalmers et al., "APOE epsilon 4 influences the pathological phenotype of Alzhemier's disease by favouring cerebrovascular over parechyma accumulation of a beta protein", Neuropathology and Applied Neurobiology, vol. 29, No. 3 pp. 231-238 (2003). |
Chang et al., "Adjuvant activity of incomplete Freund's adjuvant," Advanced Drug Delivery Reviews, 32:173-186 (1998). |
Chao et al., "Transforming Growth Factor-betaProtects human Neurons Against beta-Amyloid-Induced Injury," Soc. Neurosci. Abstracts, 19:513-7 (1993). |
Chao et al., "Transforming Growth Factor-βProtects human Neurons Against β-Amyloid-Induced Injury," Soc. Neurosci. Abstracts, 19:513-7 (1993). |
Chapman, "Model behavior," Nature, 408:915-916 (2000). |
Chauhan et al. "Intracerebroventricular Passive Immunization With Anti-β Antibody in Tg2576" J of Neuroscience 74:142-147 (2003). |
Check, "Battle of the Mind," Nature, 422:370-372 (2003). |
Check, "Nerve Inflamtion Halts Trail for Alzheimer's Drugs," Nature, 415:462 (2002). |
Check, "Nerve Inflamtion Halts Trial for Alzheimer's Drugs." Nature, 415:462 (2002). |
Chemical Abstract database, Abstract of "Injection of Newborn Mice with Seven Chemical Adjuvants to Help Determine Their Safety in Use in Biologicals," Chemical Abstract database. (Publication date unknown.). |
Chen et al., "A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease," Nature, 408(6815):975-979 (2000). |
Chen et al., "An Antibody to beta Amyloid Precursor Protein Inhibits Cell-substratum Adhesion in Many Mammalian Cell Types," Neuroscience Letters, 125:223-226 (1991). |
Chen et al., "An Antibody to β Amyloid Precursor Protein Inhibits Cell-substratum Adhesion in Many Mammalian Cell Types," Neuroscience Letters, 125:223-226 (1991). |
Chen et al., "Neurodegenerative Alzheimer-like pathology in PDAPP 717V->F transgenic mice," Progress in Brain Research, 117:327-337 (1998). |
Chen et al., "Neurodegenerative Alzheimer-like pathology in PDAPP 717V→F transgenic mice," Progress in Brain Research, 117:327-337 (1998). |
Chen et al., "Selection and Analysis of an Optimized Anti-VEGF Antibody: Crystal Structure of an Affinity-matured Fab in Complex with Antigen," J. Mol. Biol., 293:865-881 (1999). |
Chimicon International, "Mouse Anti-Amyloid Beta Protein Monoclonal Antibody," Catalog # MAB1561. |
Chishti et al., "Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695," J. Biol.Chem. 276(24):21562-70 (2001). |
Choi et al., "A Generic Intron Increases Gene Expression in Transgenic Mice," Molecular and Cellular Biology, 11(6):3070-3074 (1991). |
Chothia et al., "Domain Association in Immunoglobulin Molecules " J. Mol. Biol., 186:651-663. |
Chromy et al., "Self-assembly of Abeta (1-42) into globular neurotoxins," Biochemistry, 42(44):12749-12760 (2003). |
Chromy et al., "Self-assembly of Aβ (1-42) into globular neurotoxins," Biochemistry, 42(44):12749-12760 (2003). |
Chung et al., "Uptake, Degradation, and Release of Fibrillar and Soluble Forms of Alzheimer's Amyloid beta-Peptide by Microglial Cells," J. Biol. Chem., 274(45):32301-32308 (1999). |
Chung et al., "Uptake, Degradation, and Release of Fibrillar and Soluble Forms of Alzheimer's Amyloid β-Peptide by Microglial Cells," J. Biol. Chem., 274(45):32301-32308 (1999). |
Cirrito et al., "Amyloid beta and Alzheimer disease therapeutics: the devil may be in the details," J. Clin. Invest., 112:321-323 (2000). |
Cirrito et al., "Amyloid β and Alzheimer disease therapeutics: the devil may be in the details," J. Clin. Invest., 112:321-323 (2000). |
Citron et al., "Evidence that the 42- and 40- amino acid forms of amyloid-beta protein are generated from the beta-amytoid precursor protein by different protease activities," PNAS, 93(23):13170-13175 (1996). |
Citron et al., "Evidence that the 42- and 40- amino acid forms of amyloid-β protein are generated from the β-amytoid precursor protein by different protease activities," PNAS, 93(23):13170-13175 (1996). |
Citron, M., "Alzheimer's disease: treatments in discovery and development," Nat Neurosci., 5:1055-1057 (2002). |
Clark et al., Chemical Immunology Antibody Engineering IgG Effector Mechanisms, 65:88-110 (1997). |
Claudio, "Ultrastructural features of the blood-brain barrier in biopsy tissue for Alzheimer's disease patients." Acta Neuropathol. 91:6-14 (1996). |
Clayton et al., "Synudeins in Synaptic Plasticity and Neurodegenerative Disorders," J. Neurosci. Res., 58:120-129 (1999). |
Co et at, "Chimeric and humanized antibodies with specificity for the CD33 antigen," J. Immunol., 148:1149-1154 (1992). |
Coico et al., Immunology a Short Course, Fifth Edition, pp. 18-24 (2003). |
Colman, "Effects of Amino Acid Sequence Changes on Antibody-Antigen Interactions," Research in Immunology, 145:33-36 (1994). |
Coloma et al., "Transport Across the Primate Blood-Brain Barrier of a Genetically Engineered Chimeric Monoclonal Antibody to the Human Insulin Receptor," Pharm. Res., 17:266-274 (2000). |
Colombian Patent Application No. 98071271, Technical Opinion of Jean Paul Vernot submitted on Jun. 22, 2005 as evidence with the brief amending the nullity action (with English translation) (drafted Nov. 2004). |
Comery et al., "Passive Immunization Against β-Amyloid Leads to Acute Cognition Improvement," Society for Neuroscience, abstract, Washington DC, 11/12-16/05. |
Communication in EP 07012421.9 pursuant to Art. 94(3) EPC dated Nov. 5, 2010. |
Constantino, Expert opinion Sep. 17, 2010. |
Conway et al., "Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: Implications for pathogenesis and therapy," PNAS, 97(2):571-576 (2000). |
Conway et al., "Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: Implications for pathogenesis and therapy," PNAS, 97(2):571-576 (2000). |
Corcoran et al., "Overexpression of hAPPswe Impaires Rewarded Alternation and Contextual Fear Conditioning in a Transgenic Mouse Model of Alzheimer's Disease," Learn Mem. 9(5):243-252:2000. |
Cordell, B., "beta-Amyloid formation as a potential therapeutic target for Alzheimer's disease " Ann. Rev. Pharmacal. Toxicol. 34:69-89 (1994). |
Cordell, B., "β-Amyloid formation as a potential therapeutic target for Alzheimer's disease " Ann. Rev. Pharmacal. Toxicol. 34:69-89 (1994). |
Corey-Bloom et al., "Clinical features distinguishing large cohorts with possible AD, probable AD, and mixed dementia," J. Am. Geriatr. Soc., 41(1):31-37 Abstract (1993). |
Costa et al., "Immunoassay for transthyretin variants associated with amyloid neuropathy," Scand. J. Immunol., 38:177-182 (1993). |
Cox et al., "Adjuvants-a classification and review of their modes of action," Vaccine, 15(3):248-256 (1997). |
Cribbs et al, "All-D-Erantiomers of Beta-Amyloid Exhibit Similar Biological Properties to All-L-Beta-Amyloids," J. Biol. Chem., 272:7431-7436 (1997). |
Cribbs et al., "Adjuvant-dependant modulation of th1 and th2 responses to immunization with B-amyloid", International Immunology, 2003, vol. 15, No. 4, pp. 505-514. |
Curriculum Vitae Professor Nancy Joan Abbott, Mar. 2013. |
Daly, et al., "Detection of the membrane-retained carboxy-terminal tail containing polypeptides of the amyloid precursor protein in tissue from Alzheimer's Disease brain," Life Sci., 63:2121-2131 (1998). |
Das et al., "Amyloid-beta Immunization Effectively Reduces Amyloid Deposition in FcRgamma Knock-Out-Mice," J. Neuroscience, 23(24):8532-8538 (2003). |
Das et al., "Amyloid-β Immunization Effectively Reduces Amyloid Deposition in FcRγ Knock-Out-Mice," J. Neuroscience, 23(24):8532-8538 (2003). |
Das et al., "Reduced effectiveness of Aβ-42 immunization in APP transgenic mice with significant amyloid deposition," Neurobiology of Aging, 22:721-727 (2001). |
Database Geneseq, "Nucleotide Sequence of a Variable Heavy Chain of IgG4," EBI Accession No. GSN:ADZ51216 (2005). |
Davis, S. S., "Nasal Vaccines," Advanced Drug Delivery Reviews, 51:21-42 (2001). |
De Felice et al., "β-Amylold production, aggregation, and clearance as targets for therapy in Alzheimer's disease," Cell Mol. Neurobiol., 22(5/6):545-563 (2002). |
De La Cruz et al, "Immumogenicity and Epitope Mapping of Foreign Sequences via Genetically Engineered Filamentous Phage," J Biol Chem, 263(9):4318-4322 (1988). |
De Lustig et al., "Peripheral Markers and Diagnostic Criteria in Alzheimer's Disease: Critical Evaluations," Rev. in Neurosciences, 5:213-225 (1994). |
Deane, et al. "IgG-Assisted Age-Dependent Clearance of Alzheimer's Amyloid β Peptide by the Blood-Brain Barrier Neonatal Fc Receptor" The Journal of Neuroscience, Dec. 14, 2005 25(50):11495-11503. |
Decision of Opposition Division in EP 1 160 256 dated Feb. 17, 2011. |
Declaration by Dr. Dale Schenk dated Nov. 21, 2011. |
Declaration of Dr. Mattias Staufenbiel Ph D. Jul. 15, 2011. |
Declaration of Dr. Michael John Owen with CV and list of publications May 10, 2013. |
Declaration of Georg Friedrich Melchers with CV and list of publications Apr. 6, 2013. |
Declaration of Professor Nancy Joan Abbott, Apr. 8, 2013. |
Declaration of Shyra J. Gardai dated Mar. 2, 2009. |
Demattos et al., "Brain to plasma amyloid-beta efflux: a measure of brain amyoid burden in a mouse model of Alzheimer's disease," Science, 295(5563):2264-2267 (2002). |
Demattos et al., "Brain to plasma amyloid-β efflux: a measure of brain amyoid burden in a mouse model of Alzheimer's disease," Science, 295(5563):2264-2267 (2002). |
Demattos et al., "Peripheral Anti Abeta Antibody Alters CNS and Plasma Abeta Clearance and Decreases Brain Abeta Burden in a Mouse Model of Alzheimer's Disease " PNAS early edition, 10.1073/pnas. 151261398 (2001). |
Demattos et al., "Peripheral Anti Aβ Antibody Alters CNS and Plasma Aβ Clearance and Decreases Brain Aβ Burden in a Mouse Model of Alzheimer's Disease " PNAS early edition, 10.1073/pnas. 151261398 (2001). |
Demattos et al., "Peripheral anti-Abeta antibody alters CNS and plasma clearance and decreases Abeta burden in a mouse model of Alzheimer's disease," PNAS, 98(15):8850-8855 (2001). |
Demattos et al., "Peripheral anti-Aβ antibody alters CNS and plasma clearance and decreases Aβ burden in a mouse model of Alzheimer's disease," PNAS, 98(15):8850-8855 (2001). |
Demattos et al., "Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease " J. Neurochem., 81:229-236 (2002). |
Demattos et al., "Plaque-associated disruption of CSF and plasma amyloid-β (Aβ) equilibrium in a mouse model of Alzheimer's disease " J. Neurochem., 81:229-236 (2002). |
Dewitt et al., "Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease," Experimental Neurology, 149:329-340 (1998). |
Di Martino et al., "Production and Characterization of Antibodies to Mouse Scrapie-Amyloid Protein Elicited by Non-carrier Linked Synthetic Peptide Immunogens," J. Molecular Recognition, 4(2-3):85-91 (1991). |
Dialog/Derwent, Abstract of WPI Acc No. 1997-054436/199706: Stable vaccine compsns.-comprise a macrocyclic lactone, a milbemycin, an avermectin, an antigen, a dispersing agent, an adjuvant, a water sol. organic solvent and saline or water, Derwent File 351: Derwent WPI database. (Publication date unknown.). |
Dialog/Derwent, Abstract of WPI Acc No: 1995-261292/199534: Novel monoclonal antibody against human high-affinity IgE receptor—and DNA fragment encoding the MAb, for the specific identification of human Fc-epsilon RI, Derwent WPI database (1995). |
Dickey et al., "Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1-42 peptide," DNA and Cell Biology, 20(11):723-729 (2001). |
Dickey et al., "Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated β-amyloid 1-42 peptide," DNA and Cell Biology, 20(11):723-729 (2001). |
Dickson et al., "Neuroimmunology of Alzheimer's disease: a conference report," Neurobiology of Aging, 13(6):793-798 (1992), abstract only. |
Dictionary.com definition of "prophylactic", pp. 1-3 downloaded from internet Oct. 12, 2005. |
Diomede et al., "Activation effects of a prion protein fragment [PrP-(106-126)] on human leucocytes," Biochem. J., 320:563-570 (1996). |
Disis et al., "Granulocyte-macrophage colony-stimulating factor: An effective adjuvant for protein and peptide-based vaccines," Blood, 88(1):202-210 (1996). |
Do et al., "Reprogramming Somatic Gene Activity by Fusion With Pluripotent Cells" Stem Cell Reviews., 2:257-264 (2006). |
Dodart et al., "Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model," Nat. Neurosci. 5(5):452-457 (2002). |
Dodart et al., "Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model," Nat. Neurosci. 5(5):452-457 (2002). |
Dodart, "Immunotherapy for Alzheimer's disease: will vaccination work?," Trends in Molecular Medicine, 9(3):85-87 (2003). |
Dodel et al., "Immunotherapy for Alzheimer's disease," Lancet Neurol., 2(4):215-220 (2003). |
Dodel, et al., "Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease", J. Neurol. Neurosurg. Psychiatry, 75:1472-1474 (2004). |
Doerks et al., "Protein annotation: detective work for function prediction," Trends in Genetics, 14(16):248-250 (1998). |
Dohi et al., "Reactivity of a Mouse/Human Chimeric Anti-GM2 Antibody KM966 with Brain Tumors" Anticancer Research, 14:2577-2582 (1994). |
Donnelly, "New Developments in Adjuvants," Mechanism of Ageing and Development, 93:171-177 (1997). |
Dovey et al., "Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain," J. Neurochem., 76(1):173-181 (2001). |
Drew et al., "Vaccination by cholera toxin conjugated to a herpes simplex virus type 2 glycoprotein D peptide," Journal of General Virology, 73:2357-2366 (1992). |
Druckexemplar in EP 1 160 256 dated Jan. 25, 2010. |
Du et al., "Reduced levels of amyloid beta-peptide antibody in Alzheimer disease," Neurology,.57(5):801-5 (2001). |
Du et al., "α2-Macroglobulin as a β-Amyloid Peptide-Binding Plasma Protein," J. Neurochemistry, 69(1):299-305 (1997). |
Duff et al., "Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1," Nature, 383(6602):710-713 (1996). |
Duff et al., "Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1," Nature, 383(6602):710-713 (1996). |
Duff et al., "Mouse model made," Nature, 373:476-477 (1995). |
Dumery et al., "beta-Amyloid protein aggregation: its implication in the physiopathology of Alzheimer's disease " Pathol. Biol., 49:72-85 (2001). |
Dumery et al., "β-Amyloid protein aggregation: its implication in the physiopathology of Alzheimer's disease " Pathol. Biol., 49:72-85 (2001). |
Eck et al., Goodman and Gilman's the pharmacological basis of therapeutics, Chapter 5, pp. 77-101 (1996). |
Ecuador Patent Application No. SP 98/2764, English translation of Expert Report submitted Apr. 19, 2007 in support of the Appeal filed on Jul. 29, 2005. |
Ecuadorian Search Report of Jul. 2, 2009 for Ecuador Patent Application No. SP 03-4685. |
El-Agnaf et al., "The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's beta-amyloid peptide," Eur. J. Biochem., 256(3):560-569 (1998). |
Elan Reports First Quarter 2006 Financial Results. Business Wire (May 4, 2006) XP002620724. |
Elan Reports First Quarter 2006 Financial Results. Business Wire (May 4, 2006) XP002620725. |
Elan, "Elan and AHP Provide an Update on the Phase 2A Clinical Trial of AN-1792," Press Release. (Jan. 18, 2002). |
Elan, "Elan and Wyeth Provide Update on Status of Alzheimer's Collaboration," Press Release (Mar. 1, 2002). |
Eli Lilly and Company vs Janssen Alzheimer Immunotherapy, Approved Judgement, Case No. HC11C03400, Royal Courts of Justice, London, Jun. 25, 2013. |
Eli Lilly, "Eli Lilly and Company Announces Top-Line Results on Solanezumab Phase 3 Clinical Trials in Patients with Alzheimer's Disease" Press Release, Aug. 24, 2012. |
Elizan et al., "Antineurofilament antibodies in a postencephalitic and idiopathic Parkinson's disease," J. Neurol. Sciences, 59:341-347 (1983). |
EP 1 994 937 Decision of Oral Procedings from EPO Opposion Division dated Jul. 24, 2013. |
EP 1160256 B2 Response to Notice of Opposition Jan. 19, 2009. |
Eriksen et al., "NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo," J. Clin. Invest., 112(3):440-449 (2003). |
Esiri, "Is an effective immune intervention for Alzheimer's disease in prospect?", Trends in Pharm., Sci. 22:2-3 (2001). |
Esler et al., "Point substitution in the central hydrophobic cluster of a human β-amyloid congener disrupts peptide folding and abolishes plaque competence," Biochemistry, 35:13914-13921 (1996). |
European Examination Report as part of Dec. 8, 2008 communication for European Application 04720353.4. |
European Examination Report of Mar. 9, 2007 for European Application 01995364.5-1222. |
European Examination Report of Nov. 20, 2008 for European Application 08011409.3. |
European Examination Report of Oct. 8, 2007 for European Application 01995364.5-1222. |
European Examination Report of Sep. 23, 2008 for European Application 04776252.1-2405. |
European Examination Report of Sep. 26, 2007 for European Application 04720353.4-1222. |
European Extended Search Report of Dec. 6, 2011 for European Application 10183051.1. |
European Extended Search Report of Mar. 1, 2012 for European Application 08839961. |
European Extended Search Report of Mar. 15, 2012 for European Application 09075267.6. |
European Search Report of Feb. 7, 2011 for European Application EP 08 74 6362.6. |
European Search Report of Jan. 16, 2007 for European Application 04776252.1-2405. |
European Search REport of May 22, 2006 for European Application 06075479.3-2107. |
European Search Report of May 22, 2006 for European Application 06075704.4-2107. |
European Search Report of Oct. 25, 2013 for European Application 08746362.6. |
Extended European Search Report of Dec. 18, 2008 for European Application 05812436.6-1212. |
Extract from EPO patent register of EP 1 160 256 retrieved on Sep. 7, 2011. |
Extract from EPO patent register of EP 1 842 859 retrieved on Sep. 7, 2011. |
Extract from EPO patent register of EP1842859 Communication under Rule 71(3) Mar. 28, 2013. |
Extract from EPO patent register of EP1842859 Decision to Grant Mar. 28, 2012. |
Family and legal status of EP0613007, Inpadoc Search (2009). |
Farlow, et al., "Safety and biomarker effects of solanezumab in patients with Alzheimer's disease" Alzheimer's & Dementia, 8:261-271 (2012). |
Felsenstein et al., "Processing of the β-amyloid precursor protein carrying the familial, Dutch-type, and a novel recombinant C-terminal mutation," Neuroscience Letters, 152:185-189 (1993). |
Felsenstein et at., "Transgenic Rat and In-Vitro Studies of B-Amyloid Precursor Protein Processing;" Alzheimer's and Parkinson's Diseases, Hanin et al. Ed., pp. 401-409, Plenum Press, New York, (1995). |
Finch et al., "Evolutionary Perspectives on Amyloid and Inflammatory Features of Alzheimer Disease," Neurobiology of Aging, 17(5):809-815 (1996). |
Findeis et al, "Modified peptide inhibitors of amyloid B-peptide polymerization," Biochemistry,.38:6791-6800 (1999). |
Findeis, M. A., "Approaches to discovery and characterization of inhibitors of amyloid β-peptide polymerization," Biochem. Biophys. Acta, 1502(1):76-84 (2000). |
Fisher et al., "Expression of the amyloid precursor protein gene in mouse oocytes and embryos," PNAS, 88:1779-1782 (1991). |
Flanders et al., "Altered expression of transforming growth factor-β in Alzheimer's disease," Neurology, 45:1561-1569 (1995). |
Flood et al., "An amyloid β-Protein fragment, A β[12-28J, equipotently impairs post-training memory processing when injected into different limbic system structures," Brain Res, 663(2):271-276 (1994). |
Flood, et al, "Topography of a binding site for small amnestic peptides deduced from structure-activity studies: Relation to amnestic effect of amyloid B protein," PNAS, 91:380-384 (1994). |
Fonseca et al., "The Presence of Isoaspartic Acid in β-Amyloid Plaques Indicates Plaque Age," Experimental Neurology, 157(2):277-288 (1999). |
Foote et al., "Antibody Framework Residues Affecting the Conformation of the Hypervariable Loops," J. Mol. Biol., 224:487-499 (1992). |
Fox et al., "Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer's disease," Brain, 121:1631-1639 (1998). |
Fragione et al., Familial cerebral amyloid angiopathy related to stroke and dementia. Amyloid, 8(Suppl 1):36-42 (2001), abstract only. |
Frautschy et al., "Effects of injected Alzheimer β-amyloid cores in rat brain," PNAS, 88:8362-8366 (1991). |
Frazer et al., "Immunoglobulins: Structure and Function," chapter 3, pp. 37-74 from Fundamental Immunology, fourth edition, W.E. Paul, eds., Lippincott-Raven publishers, Philadelphia (1999). |
Frenkel et al., "Generation of auto-antibodies towards Alzheimer's disease vaccination," Vaccine, 19:2615-2619 (2001). |
Frenkel et al., "High affinity binding of monoclonal antibodies to the sequential epitope EFRH of β-amyloid peptide is essential for modulation of fibrillar aggregation," J. of Neuroimmunology, 95:136-142 (1999). |
Frenkel et al., "Immunization against Alzheimer's β-amyloid plaques via EFRH phage administration," PNAS, 97:11455-11459 (2000). |
Frenkel et al., "N-terminal EFRH sequence of Alzheimer's β-amyloid peptide represents the epitope of its anti-aggregating antibodies," J. of Neuroimmunology, 88:85-90 (1998). |
Frenkel et al., "Reduction of β-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization," Vaccine, 21(11-12):1060-1065 (2003). |
Frenkel et al., "Towards Alzheimer's β-amyloid vaccination," Biologicals, 29(3-4):243-247 (2001). |
Frenkel, et al., "Modulation of Alzheimer's β-amyloid neurotoxicity by site-directed single chain antibody," J. of Neuroimmunology, 106:23-31 (2000). |
Friedland et al., "Development of an anti-Aβ monoclonal antibody for in vivo imaging of amyloid angiopathy in Alzheimer's disease " Mol. Neurology, 9:107-113 (1994). |
Friedland, et al., "Neuroimaging of Vessel Amyloid in Alzheimer's Disease," in Cerebrovascular Pathology in Alzheimer's Disease, eds. de la Torre and Hachinski, New York Academy of Sciences, New York, New York (1997). |
Fukutani et al., "Cerebeller pathology in sporadic and familial Alzheimer's disease induding APP 717 (Val->IIe) mutation cases: a morphometric Investigation," J. Neurologic Sci. 149:177-184 (1997). |
Furlan et al., "Vaccination with amyloid-β peptide induces autoimmune encephalomyelitis in C57/BL6 mice," Brain, 126:285-291 (2003). |
Gambetti, et al., "Human brain amyloidosis," Nephrology Dialysis Transplantation, 13(Suppl. 7):33-40, (1998). |
Games et al., "Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein," Nature, 373(6514):523-527 (1995). |
Games et al., "Prevention and Reduction of AD-type Pathology in PDAPP Mice Immunized with Aβ1-42" Annals of the New York Academy of Science, 920:274-284 (2000). |
Gandy et al., "Amyloidogenesis in Alzheimer's disease: some possible therapeutic opportunities," TiPS, 13:108-113 (1992). |
Gardella et al., "Intact Alzheimer amyloid precursor protein (APP) is present in platelet membranes and is encoded by platelet nnRNA," Biochem. Biophys. Res. Comm., 173:1292-1298 (1990). |
Gaskin et al., "Human antibodies reactive with beta-amyloid protein in Alzheimer's disease," J. Exp. Med., 177:1181-1186 (1993). |
Gauthier et al., "Alzheimer's Disease: Current Knowledge, Management and Research," Can. Med. Assoc. J., 157:1047-1052 (Oct. 15, 1997). |
Geddes, "N-terminus truncated β-amyloid peptides and C-terminus truncated secreted forms of amyloid precursor protein: distinct roles in the pathogenesis of Alzheimer's disease " Neurobiology of Aging, 20:75-79 (1999). |
Geeraedts et al., "Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptors Signalling", PLoS Pathogens, 2008, 4:1-8. |
Gelinas et al., "Immunotherapy for Alzheimer's disease," PNAS, 101(suppl. 2):14657-14662 (2004). |
Genbank Accession No. AAA69734, Schroeder et al., "Immunoglobulin heavy chain [Homo sapiens], Anti-DNA immunoglobulin light chain IgG [Mus musculus]," Jul. 11, 1995. |
Genbank Accession No. AAB35009.1, Wang et al., "Antiidiotypic Ig 1F7 Light Chain Variable Region [Human, 1F7 Hybridoma Cells, Peptide Partial, 120aa]," Oct. 28, 1995. |
Genbank Accession No. AAB48800, "Anti-DNA immunoglobulin light chain IgG [Mus musculus]," Sep. 14, 2001. |
Genbank Accession No. AAD00856.1, "Igm Heavy Chain Variable Region [Homo sapiens]," Jul. 31, 2001. |
Genbank Accession No. AAD26773, "Immunoglobulin heavy chain VH3609-JH3 region [Mus musculus]," Apr. 22, 1999. |
Genbank Accession No. BAC01733, Akahori et al., "Immunoglobulin kappa light chain VLJ region [Homo sapiens]", Jul. 2, 2002. |
Genbank Accession No. CAA46659, "IgE antibody light chain(VJ)," Jun. 15, 1993. |
Genbank Accession No. X65775.1, "M.musculus DNA for IgE antibody light chain (VJ)," Jun. 15, 1993. |
GenBank, Accession No. AAA38630.1, "Immunoglobulin gamma-1 chain [Mus musculus]" May 5, 1994. |
Gerald, et al., "Alzheimer's disease market: hope deferred", Nature, vol. 12:19-20 Jan. 2013. |
Geylis et al., "Immunotherapy of Atzheimer's dsease 9AD): From murine models to anti-amyloid beta 9Ab) human monclonal antibodies,"Autoimmunity Rev., 5:33-39 (2000). |
Ghersi-Egea et al., "Fate of Cerebrospinal Fluid-Borne Amyloid β-Peptide: Rapid Clearance into Blood and Appreciable Accunulation by Cerebral Arteries,"Journal of Neurochemistry. vol. 67 No. 2:880-883 (1996). |
Ghetie et al., "CD4 Peptide-Protein Conjugates, But Not Recombinant Human CD4, Bind to Recombinant gp120 From the Human Immunodeficiency Virus in the Presence of Serum From AIDS Patients.," Proc. Natl. Acad. Sci., 88:5690-5693 (1991). |
Ghiso et al., "Epitope map of two polyclonal antibodies that recognize amyloid lesions in patients with Alzheimer's disease," Biochem. J., 282 (Pt 2):517-522 (1992). |
Ghochikyan, "Rationale for Peptide and DNA Based Epitope Vaccine for Alzheimer's Disease Immunotherapy", CNS Neurol Disord Drug Targets, 2009: 8(2): 128 1-18. |
Gibson et al., "Abnormalities in Alzheimer's Disease Fibroblasts Bearing the APP670/671 Mutation," Neurobiology of Aging, 18(6):573-580 (1997). |
Gilman, S. et al., "Clinical Effects of Aβ Immunization (AN1792) in Patients with AD in an Interrupted Trial," Neurology, 64:1553-1562 (2005). |
Giulian et al., "Specific domains of β-amyloid from Alzheimer plaque elicit neuron killing in human microglia," J Neurosci., 16 (19):6021-6037 (1996). |
Giulian, et al., "The HHQK Domain of b-Amyloid Provides a Structural Basis for the Immunopathology of Alzheimer's Disease " J. Biol. Chem.., 273:29719-29726 (1998). |
Glenn et al., "Skin immunization made possible by cholera toxin," Nature, 391:851 (1998). |
Glenner et al., "Alzheimer's Disease and Downs Syndrome: Sharing of a Unique Cerebrovascular Amyloid Fibril Protein," Biochem. Biophys. Res. Comm., 122(3): 1131-1135 (1984). |
Glenner et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein " Biochem. Biophys. Res. Comm., 120(3): 885-890 (1994). |
Gluck et al., "Immunopotentiating Reconstituted Influenza Virus Virosome Vaccine Delivery System for Immunization against Hepatitis A", J. Clin. Invest,,(1992) vol.90:2491-2495. |
Gluck, "Immunopotentiating reconstituted influenza virosomes (IRIVs) and other adjuvants for improved presentation of small antigens", Vaccine, vol. 10, Issue 13 (1992) 915-919. |
Goate et al., "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease," Nature., 349:704-706 (1991). |
Goldfarb et al., "The Transmissible Spongiform Encephalopathies," Ann. Rev. Med., 46:57-65 (1995). |
Golding et al., "Vaccine Strategies: Targeting Helper T Cell Responses," Annals New York Academy of Sciences, 31:126-137 (1995). |
Goldsby et al., "Vaccines," Chapter 18 from Immunology, 4th Edition, W.H. Freeman and Company, New York, pp. 449-465 (2000). |
Goldsteins et al., "Goldsteins et al., Éxposure of cryptic epitopes on transthyretin only in amypoid and in amyloidogenic mutants," PNAS, 96:3108-3113 (1999). |
Gong et al., "Alzheimer's disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss " PNAS, 100(18):10417-10422 (2003). |
Gonzales-Fernandez et al., "Low antigen dose favors selection of somatic mutants with hallmarks of antibody affinity maturation," Immunology, 93:149-153 (1998). |
Gorevic et al., "Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic X ray diffraction pattern" Biochem. and Biophy. Res. Commun., 147(2):854-862 1987. |
Gortner, Outlines of Biochemistry, pp. 322-323, John Wiley & Sons, Inc., New York (1949). |
Gozes et al., "Neuroprotective strategy for Alzheimer disease: Intranasal administration of a fatty neuropeptide," PNAS, 93:427-432 (1996). |
Gravina et al., "Amyloid β Protein (Aβ) in Alzheimer's Disease " J. Biol. Chem., 270(13):7013-7016 (1995). |
Greaves, et al., "Posterior reversible encephalopathy syndrome following anti-lymphocyte globulin treatment for severe aplastic anaemia" British Journal of Heamatology, Aug. 2006: 13493):251. |
Greenberg et al. "Amyloid Angiopathy-Related Vascular Congnitive Impairment" Stoke., 35:2616-2619 (2004). |
Greenberg et al., "Alzheimer disease's double-edged vaccine," Nat. Med., 9(4):389-390 (2003). |
Greisman et al., "A General Strategy for Selecting High-Affinity Zinc finger Proteins for Diverse DNA Target Sites" Science vol. 275:657-661 (1997). |
Gross et al., "Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius," Am J Physiol Regul Integr Comp Physiol, 259:R1131-R1138 (1990). |
Gross et al., "Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius," Am J Physiol Requl Integr Comp Physiol, 259:R1131-R1138 (1990). |
Grubeck-Loebenstein, et al., "Immunization with β-amyloid: could T-cell activation have a' harmful effect?", Tins, 23:114 (2000). |
Gupta et al., "Adjuvants for human vaccines—current status, problems, and future prospects," Vaccine, 13(14):1263-1275 (1995). |
Gupta et al., "Differences in the immunogenicity of native and formalized cross reacting material (CRM197) of diptheria toxin in mice and guinea pigs and their implications on the development and control of diphtheria vaccine based on CRMs," Vaccine, 15(12/13): 1341-1343 (1997). |
Gustavsson et al., "Mechanisms of Transthyretin Amyloidogenesis Antigenic Mapping of Transthyretin Pruified from Plasma and Amyloid Fibrils and within in Situ Tissure Localizations" American Journal of Pathology 44(6):1301-1311 (1994). |
Haass et al. "Amyloid beta-peptide is produced by cultured cells during normal metabolism " Nature, 359(6393):322-325 (1992). |
Haass et al., "Protofibrils, the unifying toxic molecule of neurodegenerative disorders?," Nature Neuroscience, 4(9):859-860 (2001). |
Haass, C., "New hope for Alzheimer disease vaccine " Nat Med., 8(11):1195-1196 (2002). |
Haga et al., "Synthetic Alzheimer amyloid β/A4 peptides enhance production of complement C3 component by cultured microglial cells," Brain Research, 601:88-94 (1993). |
Hagen, Declaration Oct. 31, 2011. |
Hamilton, "Molecular Engineering: Applications to the Clinical Laboratory," Clin. Chem. 39(9):1988-1997 (1993). |
Hampel et al., "Measurement of Phosphorylated Tau epitopes in the Differential Diagnosis of Alzheimer Disease", Arch Gen Psychiatry (2004) 61(1):95-102. |
Hanan and Solomon, "Inhibitory effect of monoclonal antibodies on Alzheimer's β-amyloid peptide aggregation," Int. J. Exp. Clin. Invest., 3:130-133 (1996). |
Hanes et al., "New advances in microsphere-based single-dose vaccines," Advanced Drug Delivery Reviews, 28: 97-119 (1997). |
Hara et al., "Development of a safe oral Aβ vaccine using recombinant adeno-associated virus vector for Alzheimer's disease," J. Alzheimer's Disease, 6:483-488 (2004). |
Hardy, "Amyloid, the presenilins and Alzheimer's disease," TINS, 20(4): 154-159 (1997). |
Hardy, John, "New Insights into the Genetics of Alzheimer's Disease," Annals of Med., 28:255-258 (1996). |
Harigaya, et al., "Modified amyloid β protein ending at 42 or 40 with different solubility accumulates in the brain of Alzheimer's disease," Biochem. Biophys. Res. Comm., 211:1015-1022 (1995). |
Harlow et al., eds., Antibodies: A Laboratory Manual, p. 98 (1988). |
Harlow et al., eds., Antibodies: A Laboratory Manual, pp. 139-195 (1988). |
Harlow et al., eds., Antibodies: A Laboratory Manual, pp. 71-82 (1988). |
Harlow et al., eds., Antibodies: A Laboratory Manual, pp. 71-82 (1998). |
Harrington et al., "Characterization of an epitope specific to the neuron-specific isoform of human enolase recognized by a monoclonal antibody raised against a synthetic peptide corresponding to the C-terminus of β/ A4-protein," Biochimica Biophysica Acta, 1158:120-128 (1993). |
Hartwig, "Immune ageing and Alzheimer's disease," NeuroReport, 6:1274-1276 (1995). |
Hazama, et al., "Intranasal Immunization Against Herpes Simplex Virus Infection by Using a Recombinant Glycoprotein D Fused With Immunomodulating Proteins, the B Subunit of Escherichia coliHeat-Labile Enterotoxin and Interleukin-2," Immunology, 78:643-649 (1993). |
He et al., "Humanization and pharmacokinetics of a monoclonal antibody with specificity for both E-and P- selectin," J. Immunol, 160:1029-1035 (1998). |
Hellman et al., "Allergy Vaccines—A Review of Developments," Clin. Immunother., 6(2):130-142 (Aug. 1996). |
Helmuth, "Further Progress on a β-Amyloid Vaccine," Science, 289:375 (2000). |
Herlyn et al., "Monoclonal antibodies in cell-mediated cytotoxicity against human melanoma and colorectal carcinoma," Eur. J. Immunol., 9:657-659 (1979). |
Hermanson et al., "Amino Acids as Spacers," Immobilized Affinity Ligand Techniques, section 3.1.1.5:150-152 (1992). |
Hezareh et al., "Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1," Journal of Virology, 24(75):12161-12168 (2001). |
Hilbich et al., "Aggregation and secondary structure of synthetic amylold (βA4 peptides of Alzheimer's disease," J. Mol. Biol., 218:149-163 (1991). |
Hilbich et al., "Human and rodent sequence analogs of Alzheimer's amyloid βA4 share similar properties and can be solubilized in buffers of pH 7.4," Eur. J. Biochem., 201:61-69 (1991). |
Hilbich et al., "Substitutions of hydrophobi amino acid reduce the amyloidogenicity of Alzheimer's disease βA4 peptides" J. Mol. Biol, 228:460-473 (1992). |
Hillen-Maske et al., "Konichalcit", Rompp Chemie Lexilkon, 9th edition, p. 2322 (1990). |
Hirschfield et al., "Amylodiosis: new strategies for treatment," Int. J. Biochem. & Cell Biol., 35:1608-1613 (2003). |
Hock et al., "Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease," Neuron, 38:542-554 (2003). |
Hock et al., "Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease," Nat. Med., 8(11):1270-1275 (2002). |
Hogarth, Fc Receptors are Major Mediators of Antibody Based Inflammation in Autoimmunity, Current Opinion in Immunology, 14:798-802 (2002). |
Holm et al., "Functional Mapping and Single Chain Construction of the Anti-Cytokeratin 8 Monoclonal Antibody TS1," Mol. Immunol., 44(6):1075-1084 (Feb. 2007). |
Holmes et al., "Long-term Effects of Aβ42 Immunisation in Alzheimer's Disease: Follow-up of a Randomised, Placebo-controlled Phase I Trial, " Lancet, 372: 216-223 (2008). |
Holtzman et al., "Aβ immunization and anti-Aβ antibodies: potential therapies for the prevention and treatment of Alzheimer's disease," Advanced Drug Delivery Reviews, 54:1603-1613 (2002). |
Hopp et al., "Prediction of protein antigenic determiniants from amino acid sequences," Proc. Natl. Acad. Sci. USA 78:3824-3828 (1981). |
Hsiao et al., "Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice," Science, 274: 99-102 (1996). |
Huang et al., "Amyloid β-Peptide Possesses a Transforming Growth Factor-β-Activity," The Journal of Biological Chemistry, 273(42):27640-27644 (Oct. 16, 1998). |
Huberman et al., "Correlation of cytokine secretion by mononuclear cells of Alzheimer's patients and their disease stage," J. Neuroimmunology, 52:147-152 (1994). |
Hudson et al., "Antibody as a Probe," Practical Immunology, Chapter 2, pp. 34-85 (1989). |
Human Immunology & Cancer Program brochure, from the University of Tennessee Medical Center/Graduate School of Medicine, Knoxville, Tennessee (publication date unknown). |
Hussain et al., "Selective Increases in Antibody Isotopes and Immunoglobulin G Subclass Responses to Secreted Antigens in Tuberculosis Patients and Healthy Household Contacts of the Patients," Clinical and Diagnostic Laboratory Immunology, 2(6): 726-732 (1995). |
Hyman et al., "Molecular Epidemiology of Alzheimer's Disease," N. E. J. Medicine, 333(19):1283-1284 (1995). |
Hyman, et al. "Kunitz Protease Inhibitor-Containing Amyloid β Protein Precursor Immunoreactivity in Alzheimer's Disease", J. of Neuropathology, 51(1):76-83 (1992). |
Hyslop et al., " Will Anti-amyloid Therapies Work for Alzheimer's Disease?," Lancet, 372:180-182 (2008). |
Hyslop et al., "Antibody Clears Senile Plaques" Nature, vol. 400, Jul. 8, 1999, p. 116-117. |
Ida et al., "Analysis of Heterogeneous βA4 Peptides in Juman Cerebrospinal Fluid and Blood by a Newly Developed Sensitive Western Blot Assay " J. Biol. Chem., 271(37):22908-22914 (1996). |
Idusogie et al., "Mapping of the C1q Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc," J. Immunology, 164:4178-4184 (2000). |
Ikeda, et al., "Immunogold labeling of cerebrovascular and neuritic plaque amyloid fibrils in Alzheimer's disease with an anti-8 protein monoclonal antibody," Lab. Invest., 57:446-449 (1987). |
Invitrogen Data Sheet, "Mouse anti-β-Amyloid Peptide", Catalog No. 13-0100Z (Rev Oct. 2008) DCC-08-1089. |
Irizarry et al., "Alzheimer disease therapeutics," J. Neuropathol. Exp. Neurol., 60(10):923-928. |
Irizarry et al., "Aβ Deposition is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse," J. Neuroicience, 17(18):7053-7059 (1997). |
Itagaki et al., "Relationship of microglia and astrocytes to amyloid deposits of Alzheimer's disease," J. Neuroimmunology, 24:173-182 (1989). |
Iwatsubo et al., "Visualization of Aβ(43) and Aβ840 in Senile Plaques with End-Specific Aβ Monoclonals: Evidence That an Initially Deposited Species is Aβ 42(43)," Neuron, 13:45-53 (1994). |
Jacobsen, et al., "Reversal of CM Deficits: A) 2nd Generation of mAbs to central AB epitopes B) PSAPP (18 mo) by 12A11 hv. 1. 0 & m266",Wyeth Presentation Apr. 27, 2004. |
Jagust et al., "Brain Imaging Evidence of preclinical Alzheimer's disease in normal aging" Ann Neurol, (2006) 59:67-681: abstract p. 676, table 1. |
Jahrling et al., "Opsonization of Alphaviruses in Hamsters," J. Medical Virology, 12:1-16 (1983). |
Jakes et al., "Characterisation of an Antibody Relevant to the Neuropathology of Alzheimer Disease," Alzheimer Disease and Associated Disorders, 9(1):47-51 (1995). |
Janeway et al., Immunobiology, 3rd edition, pp. 2:7, 2:9, 2:12, 8:16-8:17, 12:43 (1997). |
Janeway et al., Immunobiology, 3rd edition, pp. 8:32-8:36 (1997). |
Janeway et al., Immunobiology, 3rd eidition, pp. 8:18-8:19 (1997). |
Janeway, et al., Basic Concepts in Immunology; pp. 1:21-1:13and 8:1-8:2 (1997). |
Janeway, et al., Immunobiology: The Immune System in Health and Disease 3rd Edition; cover pages and pp. 3.22-3.27 (1997). |
Jansen et al., "Immunotoxins: Hybrid Molecules Combining High Specificity and Potent Cytotoxicity," Immun. Rev., 62: 185-216 (1982). |
Jansen et al., "Use of Highly Encapsulated Streptococcus pneumoniaeStrains in a Flow-Cytometric Assay for Assessment of the Phagocytic Capacity of Serotype-Specifid Antibodies," Clinical & Diagnostic Lab. Immunol., 5(5):703-710 (1998). |
Janssen Alzheimer Immunotherapy Research & Development, LLC, "AAB-001 in Patients With Mild to Moderate Alzheimer's Disease", Clinical Trials Gov, NIH, 2005, [retrieved on Jun. 19, 2012] Retrieved from the Internet: <http://clinicaltrials.gov/ct2/show/NCT00112073?term=aab-001&rant=3>. |
Janus et al., "A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease," Nature, 408(6815):979-982 (2000). |
Janus et al., "Transgenic mouse models of Alzheimer's Disease," Physiol. Behav., 73(5):873-886 (2001). |
Jarrett et al., "The Carboxy Terminus of the β Amyloid Protein is Critical for the Seeding of Amyloid Formation: Implications for the Pathogenesis of Alzheimer's Disease," Biochemistry, 32:4693-4697 (Nov. 5, 1993). |
Jefferis, "Antibody therapeutic: isotype and glycoform selection", Expert Opin. Biol. Ther. 7(9):1401-1413 (2007). |
Jen, et al., "Preparation and purification of antisera against different regions or isoforms of b-amyloid precursor protein," Brain Research Protocols, 2:23-30 (1997). |
Jennings, "Review of Selected Adjuvants Used in Antibody Production," ILAR Journal, 37(3) (1995). |
Joachim et al., "Antibodies to Non-beta Regions of the Beta-amyloid Precursor Protein Detect a Subset of Senile Plaques," Am. J. of Pathology, 138:373-384 (1991). |
Jobling et al., "Analysis of structure and function of the B subunit of cholera toxin by the use of site-directed mutagenesis," Molecular Microbiology, 5(7):1755-1767 (1991). |
Johnson & Johnson, "Johnson & Johnson Announces Discontinuation of Phase 3 Development of Bapineuzumab Intravenous (IV) in Mild-to-Moderate Alzheimer's Disease", Press Release, Aug. 6, 2012. |
Johnson-Wood et al., "Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease " PNAS, 94:1550-1555 (1997). |
Johnstone et al., "Nuclear and Cytoplasmic Localization of the β-Amyloid Peptide (1-43) in Transfected 293 Cells," Biochem. Biophys. Res. Comm., 220:710-718 (1996). |
Jorbeck et al., "Artificial Salmonella Vaccines: Salmonella typhimurium O-antigen-Specific Oligosaccharide-Protein Conjugates Elicit Opsonizing Antibodies that Enhance Phagocytosis," Infection and Immunity, 32(2):497-502 (1981). |
Jung et al., "Alzheimer's Beta-amyloid Precursor Protein is Expressed on the Surface of Immediately Ex Vivo Brain Cells: a Flow Cytometric Study," J. Neurosci. Res., 46(3):336-348 (1996). |
Kajkowski et al., "β-Amyloid Peptide-induced Apoptosis Regulated by a Novel Protein Containing a G Protein Activation Module," J. Biol. Chem., 276(22):18748-18756 (2001). |
Kalaria, R. N., "Serum amyloid P and related molecules associated with the acute-phase response in Alzheimer's disease," Res. Immunology, 143:637-641 (1992). |
Kalback et al., "APP Transgenic Mice Tg2576 Accumulate Aβ Peptides That are Distinct from the Chemically Modified and Insoluble Peptides Deposited in Alzheimer's Disease Senile Plagues," Biochemistry 41:922-928 (2002). |
Kallberg et al., "Prediction of Amyloid Fibril-Forming Proteins," The Journal of Biological Chemistry, 276(16):12945-12950 (Apr. 20, 2001). |
Kambhampaty, "Roche's gantenerumab could face similar fate as failed drug bapineuzumab in Alzheimer's, experts say," Retrieved from the Internet http://sussexdrugdiscovery.wordpress.com/tag/bapineuzumab, (retrieved on Sep. 27, 2013) Jul. 5, 2013. |
Kardana et al., "Serum HCG β-Core Fragment is Masked by Associated Macromolecules," Journal of Clinical Endocrinology and Metabolism, 71(5):1393-1395. |
Karran, "Current status of vaccination therapies in Alzheimer's disease" Journal of Neurochemistry, 123:647-651 (2012). |
Kascsak et al., "Mouse Polyclonal and Monoclonal Antibody to Scrapie-Associated Fibril Proteins," J. Virology, 61(12):3688-3693 (1987). |
Katzav-Gozansky et al., "Effect of monoclonal antibodies in preventing carboxypeptidase A aggregation," Biotechnol. Appl. Biochem., 23:227-230 (1996). |
Kawabata et al., "Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein," Nature, 354:476-478 (1991). |
Kayed et al., "Conformational Transitions of Islet Amyloid Polypeptide (IAPP) in Amyloid Formation In Vitro," J. Mol. Biol., 287:781-796 (1999). |
Kelly, J. W., "Alternative conformations of amyloidogenic proteins govern their behavior " Current Opinion in Structural Biology, 6:11-17 (1996). |
Kerchner, et al., "Bapineuzumab", NIH Public Access, Expert Opin Biol Ther., 10(7) 1121-1130 Jul. 2010. |
Kettleborough et al., "Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation," Protein Engineering4(7):773-783 (1991). |
Khan et al., "Immunopotentiation and Delivery Systems for Antigens for Single-Step Immunization: Recent Trends and Progress," Pharmaceutical Research, 11(1):2-11 (1994). |
Khatoon et al., "Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer's disease and control brains," FEBS Letters, 351:80-84 (1994). |
Kida, et al., "Early amyloid-β deposits show different immunoreactivity to the amino- and carboxy- terminal regions of b-peptide in Alzheimer's disease and Down's syndrome brain " Neuroscience Letters, 193:105-108 (1995). |
Kim et al., "In Vivo Engineering of a Cellular Immune Response by Coadministration of 1L-12 Expression Vector with a DNA Immunogen," J. Immunol., 158:816-826 (1997). |
Kimchi et al., "Analysis of cerebral amylold angiopathy in a transgenic mouse model of Alzheimer disease using in vivo multiphoton microscopy," J. Neuropath Exp. Neurol., 60(3):274-279 (2001). |
Kinnecom et al., "Course of Cerebral Amyloid Angiopathy? Related Inflation," Neurology, 68(17):1411-1416 (2007). |
Kirschner, et al., "Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro", Proc. Natl. Acad. Sci. USA, 84:6953-6957. |
Klafki et al., "Therapeutic approaches to Alzheimer's disease" Brain 129:2840-2825 (2006). |
Klein et al., "Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?," Trends in Neurosciences, 24(4):219-224 (2001). |
Klyubin et al., "Anti-Aβ Antibodies Prevent Block of Long-Term Potentiation in the CA1 Area of Rat Hippocampus InVivo by naturally Produced Aβ Oligomers, " Neurobiology of Aging, 25:S224-S225, abstract P2-004, pp. S224-S225 (2004). |
Kofke et al., "Remifentanil-Induced Cerebral Blood Flow Effects in Normal Humans: Dose and ApoE genotype," Neurosurg Anesthes Neurosci., 105(1):167-175 (2007). |
Kofler et al., "Immunoglobulin k Light Chain Variable Region Gene Complex Organization and Immunoglobulin Genes Encoding Anti-DNA Autoantibodies in Lupus Mice," J. Clin. Invest., 82:852-860. |
Kofler et al., "Mechanism of Allergic Cross-Reactions—III. cDNA Cloning and Variable-Region Sequence Analysis of Two IgE Antibodies Specific for Trinitrophenyl," Mol. Immunology, 29(2):161-166 (1992). |
Koller et al., "Active Immunization of Mice with a Aβ-Hsp70 Vaccine," Neurodegenerative Disases, 1:20-28 (2004). |
Konig et al., "Development and Characterization of a Monoclonal Antibody 369.2B Specificfor the Carboxyl-Terminus of the βA4 Peptide," Annals of NY Acad. Sci., 777:344-355 (1996). |
Kotilinek et al., "Reversible memory loss in a mouse transgenic model of Alzheimer's disease," J. Neurosci., 22(15):6331-6335 (2002). |
Koudinov et al., "The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma," Biochem. & Biophys. Res. Comm, 205:1164-1171 (1994). |
Kovács et al., "Mutations of the Prion Protein Gene Phenotypic Spectrum," J. Neurol., 249:1567-1582 (2002). |
Krishnan et al., "Correlation Between the Amino Acid Position of Arginine in VH-CDR3 and Specificity for Native DNA Among Autoimmune Antibodies1,2," J. Immunol., 157(6):2430-2439 (1996). |
Kuby, Immunology, 2nd Ed., Freeman pp. 126 and 168-171 (1994). |
Kuby, J., eds., p. 123 from Immunology, Third Edition, W.H. Freeman & co., (1997). |
Kuby, J., eds., pp. 108-109, 131-132 from Immunology, Third Edition, W.H. Freeman & co., (1997). |
Kuo et al., "Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains," J. Biol. Chem., 276(16):12991-12998 (2001). |
Kuo et al., "High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease," Biochem. Biophys. Res. Comm., 257(3):787-791 (1999). |
Kuo et al., "Water-soluble Aβ (N-40, N-42) Oligomers in Normal and Alzheimer Disease Brains," J. Biol. Chem., 271(8):4077-4081 (1996). |
Kurashima et al., "Production of Monoclonal Antibody against Amyloid Fibril Protein and Its Immunohistochemical Application " Appl. Pathol., 3(1-2):39-54 (1985). |
LaDu et al., "Isoform-specific Binding of Apolipoprotein E to β-Amyloid," J. Biol. Chem., 269(38):23403-23406 (1994). |
Laino, "Cerebral Edema Common, but Found to Be Manageable, With Bapineuzumab", Neurology Today, Aug. 19, 2011. |
Lambert et al., "Diffusible, nonfibrillar ligands derived from Aβ-42 are potent central nervous system neurotoxins " PNAS, 95:6448-6453 (1998). |
Lambert et al., "Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies," J. Neurochem., 79:595-605 (2001). |
Lampert-Etchells et al., "Regional Localization of Cells Containing Complement C1q and C4 mRNAs in the Frontal Cortex During Alzheimer's Disease," Neurodegeneration, 2:111-121 (1993). |
Landolfi et al., "The Integrity of the Ball-and Socket Joint Between V and C Domains is Essential for Complete Activity of a Humanized Antibody," J. Immunology, 166(3):1748-1754 (2001). |
Langer, "New Methods of Drug Delivery," Science, 249:1527-1532 (1990). |
Lannfelt et al., "Alzheimer's disease: molecular genetics and transgenic animal models," Behavioural Brain Res., 57:207-213 (1993). |
Lansbury, Peter T., "Inhibition of amyloid formation: a strategy to delay the onset of Alzheimer's disease," Curr. Ops. in Chemical Biology, 1:260-267 (1997). |
Lavie et al., "EFRH-Phage Immunization of Alzheimer's Disease Animal Model Improves Behavioral Performance in Morris Water Maze Trials " J. Moleicular Neuroscience, 24:105-113 (2004). |
Lee et al., "Aspects of Immunobiology and Immunotherapy and Uses of Monoclonal Antibodies and Biologic Immune Modifiers in Human Gliomas" Neurologic Clinics, vol. 3, No. 4, Nov. 1985, 901-917. |
Lee et al., "Aβ immunization: Moving Aβ peptide from brain to blood " PNAS, 98(16):8931-8932. |
Lemere et al., "Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans", Rejuvenation Research 9(1):77-84 (2006). |
Lemere et al., "Intranasal immunotherapy for the treatment of Alzheimer's disease: Escherichia coil Lt and LT and LY(R192G) as mucosa! adjuvants," Neurobiology of Aging, 23(6):991-1000 (2002). |
Lemere et al., "Mucosal Administration of Aβ Peptide Decreases Cerebral Amyloid Burden in Pd-App Transgenic Mice," Society for Neuroscience Abstracts, 25(part )I, Abstract 519.6, 29th Annual Meeting, (Oct. 23-28, 1999). |
Lemere, "Developing novel immunogens for a safe and effective Alzheimer's disease vaccine" Prog Brain Res. 2009; 175: 83 1-13. |
Lemere, et al., "Nasal Aβ treatment induces anti-Aβ antibody production and decreases cerebral amyloid burden in PD-APP mice," Annals of the NY Acad. Sci., 920:328-331 (2000). |
Leverone et al., "Aβ1-15 is less in nunogenic than Aβ1-40/42 for intranasal immunization of wild-type mice but may be effective for boosting'," Vaccine, 21:2197-2206 (2003). |
Levey, A. I., "Immunization for Alzheimer's disease: A shot in the arm or a whiff?," Ann. Neurology, 48(4):553-555 (2000). |
Levitt, M., "Molecular dynamics of native protein," J. Mol . Biol., 168:595-620 (1983). |
Li et al., "Thermal Stabilization of Carboxypeptidase A as a Function of PH and Ionic Milieu," Biochem Mol. Biol. Int., 43(3):601-611 (1997). |
Licastro et al., "Is immunotherapy an effective treatment for Alzheimer's disease?," Immunity & Aging, 1:1-2 (2004). |
Linke, "Monoclonal antibodies against amyloid fibril protein AA. Production, specificity, and use for immunohistochemical localization and classification of AA-type amyloidosis," J. Histochemistry and Cytochemistry32(3):322-328 (1982). |
Liu et al., "Amyloid β peptide alters intracellular vesicle trafficking and cholesterol homeostasis" Proc.Natl. Acad. Sci., 95:13266-13271 (1998). |
Livingston et al., "The Hepatitis B Virus-Specific CTL Responses Induced in Humans by Lipopeptide Vaccination Are Comparable to Those Elicited by Acute Viral Infection," J. Immunol., 159:1383-1392 (1997). |
Lo et al., "High level expression and secretion of Fc-X fusion proteins in mammalian cells " Protein Engineering, 11(6):495-500 (1998). |
Lopez et al., "Serum auto-antibodies in Alzheimer's disease " Acta. Neurol. Scand., 84:441-444 (1991). |
Lu, "In Vitro Binding Analysis of LY2062430: Surface Plasmon Resonance and FACS Analysis" Report: bTDR185 Eli Lilly and Company Apr. 2012. |
Lue et al., "Soluble β-amyloid Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease " Am. J. Pathol., 155:853-562 (1999). |
MacCallum et al., Antibody-antigen Interactions: Contact Analysis and Binding Site Topograph, 262:732-745 (1996). |
Maggio et al., "Brain Amyloid—A Physicochemical Perspective," Brain Pathology, 6:147-162 (1996). |
Majocha et al., "Development of a Monoclonal Antibody Specific for β/A4 Amyloid in Alzheimer's. Disease Brain for Application to In Vitro Imaging of Amyloid Angiopathy," The J. of Nuclear Med., 33:2184-2189(1992). |
Mak, et al., "Polyclonals to b-amyloid (1-42) identify most plaque and vascular deposits in Alzheimer cortex, but not striatum," Brain Research, 667:138-142 (1994). |
Mamikonyan et al., "Anti-Aβ1-11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers," J Biol Chem, 282(31) 22376-22386 (2007). |
Mandel et al., "Clinical trials in neurological disorders using AAV vectors: promises and challenges," Curr. Opin. Mol. Ther., 6(5):482-490 (2004). |
Mann et al., "Atypical Amyloid (ABeta) Deposition in the cerebellum in Alzheimer's Disease: An Immunohistochemical Study Using End-Specific ABeta Monoclonal Antibodies," ACTA Neuropathologica, 91:647-653 (1996). |
Mann et al., "Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutatuibs in the amyloid precursor protirn gene," The American Journal of Pathology APR, 4(148): 1257-1266. |
Mann, et al., "Amyloid βprotein (Aβ) deposition in chromosome 14-linked Alzheimer's disease: Predominance of Aβ42(43)," Annals of Neurolog,y 40:149-156 (1996). |
Mann, et al., "The extent of amyloid deposition in brain in patients with Down's syndrome does not depend upon the apolipoprotein E genotype," Neuroscience Letters, 196:105-108 (1995). |
Manning et al., "Genetic Immunization with Adeno-Associated Virus Vectors Expressing Herpes Simplex Virus Type 2 Glycoproteins B and D," Journal of Virology, 71(10):7960-7962 (1997). |
Manoj et al., "Approaches to Enhance the Efficacy of DNA Vaccines," Critical Rev. Clin. Lab. Sci., 41(1):1-39 (2004). |
Marhaug et al., "Monoclonal hybridoma antibodies to human amyloid related protein SAA " Clin. Exp. Immunol., 50(2):390-396 (1982). |
Marotta et al., "Overexpression of amyloid precursor protein A4 (β-amyloid) immunoreactivity in genetically transformed cells: Implications for a cellular model of Alzheimer amyloidosis," PNAS, 86:337-341 (1989). |
Marshall, E., "Gene Therapy's Growing Pains," Science, 269:1050-1055 (1995). |
Marx et al., "Immune recognition of the Alzheimer amyloid β protein" Poster presentation; Autoreactive T. cells P.5.18.03 Jun. 25, 1997. |
Marx et al., "The Possible Role of the Immune System in Alzheimer's Disease" Exp Gerontology, vol. 33, Nos. 7/8 pp. 871-881, 1998. |
Masliah et al., "Amyloid Protien Precursor Stimulates Excitatory Amino Acid Transport," The Journal of Biological Chemisrty, 273(20):12548-12554 (1998). |
Masliah et al., "Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F β-Amyloid Precursor Protein and Alzheimer's Disease," J. Neuroscience, 16(18):5795-5811 (1996). |
Masliah et al., "β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease," PNAS, 98(21):12245-12250 (2001). |
Masters et al., "Amyloid Plaque core protein in Alzheimer Disease and Down Syndrome," PNAS, 82:4245-4249 (1985). |
Mattson et al., "Good and bad amyloid antibodies," Science, 301(5641):1845-1849 (2003). |
Mattson, "Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives " Physiol Rev., 77(4):1081-132 (1997). |
Maury et al., "Immunohistochemical Localization of Amyloid in Finnish Hereditary Amyloidosis with Antibodies to Gelsolin Peptides," Laboratory Investigation, 64(3):400-404 (1991). |
Mavragani et al., "A Case of Reversible Posterior Leucoencephalopathy Syndrome After Rityximab Infusion," Rheumatology, 43(11) 1450-1451 (2006). |
McGee et al., "The encapsulation of a model protein in poly (D, L lactide-co-glycolide) microparticles of various sizes: an evaluation of process reproducibility," J. Micro. Encap., 14(2):197-210 (1997). |
McGeer, et at., "Immunohistochemical localization of beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy," J. of Neuroscience Res., 31:428-442 (1992). |
McLaurin et al., "Therapeutically effective antibodies against amyloid- β peptide target amyloid- β residues and 4-10 and inhibit cytotoxicity and fibrillogenesis," Nat Med., 8(11):1263-1269 (2002). |
McLean et al., "Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease," Amer. Neurological Assoc, 46:860-866 (1999). |
McNeal et al., "Stimulation of local immunity and protection in mice by intramuscular immunization with triple- or double-layered rotavirus particles and QS-21," Virology, 243:158-166 (1998). |
Meda et al., "Activation of microglial cells by β-amyloid protein and interferon-γ," Nature, 374:647-650 (1995). |
Mena, et al., "Monitoring pathological assembly of tau and β-amyloid proteins in Alzheimer's disease," Acta Neuropathol., 89:50-56 (1995). |
Merluzzi, et al., "Humanized antibodies as potential drugs for therapeutic use," Adv Clin Path., 4(2):77-85 (2000). |
Merriam-Webster online medical dictionary, entry for "cure", accessed Sep. 5, 2006. |
Miller et al., "Antigen-driven Bystander Suppression after Oral Administration of Antigens," J. Exp. Med., 174:791-798 (1991). |
Miller et al., "Comparative efficancy of two immunocontraceptive vaccines" Vaccine, (1997) 15(17-18):1858-1862 (abstract only). |
Misra et al., "Drug Delivery to the Central Nervous System: A review," J. Pharm Pharm Sci., 6(2):252-273 (May 2003). Abstract. |
Mitchell et al, "Prevention of Intracerebral Hemorrhage," Current Drug Targets, 8(7):832-838 (2007). |
Monsonego et al., "Immune hyporesponsiveness to amyloid β-peptide in amyloid precursor protein transgenic mice: Implications for the pathogenesis and treatment of Alzheimer's disease," PNAS, 98(18):10273-10278 (2001). |
Monsonego et al., "Immunotherapeutic approaches to Alzheimer's disease," Science, 302(5646):834-838 (2003). |
Monsonego et al., "Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer's disease," J. Clin. Invest., 112(3):415-422 (2003). |
Moretto, et al., "Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide", J of Biological Chemistry, 282(14):11436-11445 (2007). |
Morgan et al., "The N-terminal end of the CH2 domain of chimeric human IgG1 anti-HLA-DR is necessary for C1q, FcγRII and FcγRll binding," Immunology, 86:319-324 (1995). |
Morgan, et.al., "A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease," Nature, 408(6815):982-985 (2000). |
Mori et al., "Mass Spectrometry of Purified Amyloid β Protein in Alzheimer's Disease," J. Biol. Chem.,.267(24):17082-17088 (1992). |
Morris, et al. "The Consortium to Establish a registry for Alzheimer's Disease (CERAD)," Neurology., 39:1159-1165 (1989). |
Mount et al. "Alzheimer disease: progress or profit?" Market Analysis Nature Medicine 12(7) 780-784 (Jul. 2006). |
Movsesyan et al., "Reducing AD-Lide Pathology in 3xTg-AD Mouse Model by DNA epitope Vaccine—A Novel Immunotherapeutic Strategy", PloS ONE, 2008, vol. 3, issue 5, e2124 1-13. |
Muhs, et al., "Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in AAP transgenic mice", PNAS, Jun. 5, 2007, vol.104:23 pp. 9810-9815. |
Munch et al., "Potentional neurotoxic inflammatory response to Aβ vaccination in humans " J. Neural Transm., 109:1081-1087 (2002). |
Munson eds., Principals of Pharmacology: Basic Concepts & Clinical Applications, pp. 47-48, Chapman & Hall, New York, New York (1995). |
Murphy et al., "Development of a Monoclonal Antibody Specific for the COOH-Terminal of β-Amyloid 1-42 and Its Immunohistochemical Reactivity in Alzheimer's Disease and Related Disorders," Am. J. Pathology, 144(5):1082-1088 (1994). |
Mutschler et al., "Arzneimittel-Wirkungen, Lehrbuch der Pharmakologie und Taxiklogie," Wissenschftliche Verlagsgesellschaft mbH Stuttgart, 6th edition, pp. 651-656 (1991), (German Article). |
Mutschler et al., Drug Actions: Basic Principles and Therapeutic Aspects pp. 7, 11-12, Medpharm Scientific Publishers, Stuttgart, Germany (1995). |
Myers et. al., "Targeting Immune Effector Molecules to Human Tumor Cells Through Genetic Delivery of 5T4-Specific SCFV Fusion Protiens," Cancer Gene Therapy, 9(11):884-896 (2002). |
Nakamura et al., "Histopathological studies on senile plaques and cerebral amyloid angiopathy in aged cynomologus monkeys," Exp. Anim., 43:711-718 (1995). |
Nakamura, et al., "Carboxyl end-specific monoclonal antibodies to amyloid β protein (Aβ) subtypes (aβ40 and aβ42(43) differentiate Ab in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys," Neuroscience Letters, 201:151-154 (1995). |
Nakayama et al., "Histopathological studies of senile plaques and cerebral amyloidosis in cynomolgus monkeys," J. of Med. Primatology, 27:244-252 (1998). |
Nalbantoglu, J., "Beta-amyloid protein in Alzheimer's disease," Can. J. Neurol. Sci., 18(3 suppl.):424-427 (1991), abstract only. |
Nashar et al., "Current progress in the development of the B subunits of cholera toxin and Escherichia coli heat-labile enterotoxin as carries for the oral delivery of herterologous antigens and epitopes," Vaccine, 11(2):235-40 (1993), abstract only. |
Naslund et al., "Correlation between elevated levels of amyloid pβ peptide in the brain and cognitive decline " J. Am. Med. Assoc., 283:1571 (2000). |
Nathanson et al., "Bovine Spongiform Encephalopathy (BSE): Causes and Consequences of a Common Source Epidemic," Am. J. Epidemiol., 145(11):959-969 (1997). |
New York Times National, "Anti-Inflammatory Drugs May Impede Alzheimer's," (Feb. 20, 1994). |
Newcombe et al., "Solubility characteristics of isolated amyloid fibrils," Biochim. Biophys. Acta, 104:480-486 (1965). |
Ngo et al., "Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox," pp. 492-495 from Chapter 14 of The Protein Folding Problem and Tertiary Structure Prediction, Merz et al., eds., Birkhauser Boston (1994). |
Nicoll et al., "Neuropathology of human Alzheimer's disease after immunization with amyloid-βpeptide: a case report," Nature Medicine, 9(4):448-452 (2003). |
Niemann, "Transgenic farm animals get off the ground;" Transgenic Research, 7:73-75 (1998). |
Novartis, "Novartis MF59Tm—Adjuvanted Influenza Vaccine (Fluad®) Significantly Reduces Hospitalization in Elderly," Novartis Press Release, Oct. 19, 2007. |
Novotny et al., "Structural invariants of antigen binding: Comparison of immunoglobulin VL-VH and VL-VL domain dimmers," PNAS, 82:4592-4596 (1985). |
Oh, et al., "Reversible leukoencephalopathy associated with cerebral amyloid angiopathy", Neurology, 62 (Feb. 2004) 494-497. |
Okie. S., "Promising Vaccine Targets Ravager of Minds," Washington Post, p. A01, May 8, 2001. |
Okura et al., "Nonviral Aβ DNA vaccine therapy against Alzheimer's disease: Long-term effect and safety," PNAS, 103(25):9619-9624 (2006). |
Orgogozo, et al., "Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization" Neurology, 61:46-54 (2003 ). |
Orkin et al., Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy, Dec. 7, 1995. |
Orlandi et al., "Cloning immunoglobulin variable domains for expression by the polymerase chain reaction," PNAS, 86:3833-3837 (1989). |
Ou et al., "Aβ42 gene vaccination reduces brain amyloid plaque burden in transgenic mice," J. Neurological Sciences, 244:151-158 (2006). |
Padlan et al., Structure of an Antibody-Antigen Complex: Crystal Structure of the HyHEL-10 Fab-lysozyme Complex, Immunology, 86:5938-5942 (1989). |
Paganetti et al., "Amyloid precursor protein truncated at any of the γ-secretase sites is not cleaved to β-amyloid," J. Neurosci. Res., 46(3):283-293 (1996). |
Palha et al., "Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidiotic polyneuropathy, " J. Mol. Med., 7:703-707 (2001). |
Pallitto et al., "Recognition sequence design for peptidyl modulators of β-amyloid aggregation and toxicity," Biochemistry, 38(12):3570-3578 (1999). |
Pan et al., "Antibodies to β-Amyloid Decrease the Blood-to-Brain Transfer of β-Amyloid Peptide, " Exp. Biol. Med., 227(8):609-615 (2002). |
Pangalos et al., "Disease Modifiying Strategies for the Treatment of Alzheimer's Disease Targeted at Modulating Levels of β-amyloid Peptide," Biochemical Socity Transactions, 33(4):553-558 (2005). |
Panka et al., "Variable region framework differences result in decreased or increased affinity of variant anti-digoxin antibodies," PNAS, 85:3080-3084 (1998). |
Pardridge et al., "Chimeric peptides as a vehicle for peptide pharmaceutical delivery through the blood-brain barrier," Biochem. Biophys. Res. Comm., 146:307-313 (1987). |
Pardridge et al., "The Blood-Brain Barrier: Bottleneck in Brain Drug Development," J. Am. Soc. Exp. Neurotherapeutics, 2:3-14 (2005). |
Paresce et al., "Microglial cells influence aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor," Neuron, 17:553-565 (Sep. 1996). |
Parnetti et al., "Cognitive Enhancement Therapy for Alzheimer's Disease, The Way Forward," Drugs, 53(5):752-768 (1997). |
Pascalis et al., "Grafting of "Abbreviated" Complementarity-Determining Containing Specifictiy-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody," The Journanal Immunology, 169:3076-3084 (2002). |
Patentee's Grounds of Appeal in EP Patent No. 1 033 996 dated Jul. 18, 2011. |
Paul et al., "Transdermal immunization with large proteins by means of ultradeformable drug carriers," Eur. J. Immunol., 25: 3521-3524 (1995). |
Paul, W. E., eds., Fundamental Immunology, Third Edition, pp. 292-295, Raven Press, New York. (1993). |
PCT International Preliminary Examination Report of Feb. 9, 2004 for application PCT/US01/46587. |
PCT International Preliminary Report on Patentability (Chapter I) and Written Opinion Completed Dec. 22, 2008 for PCT/US2008/080370. |
PCT International Preliminary Report on Patentability (Chapter I) of Feb. 2, 2010 for application PCT/US07/09499. |
PCT International Preliminary Report on Patentability (Chapter I) of Jul. 31, 2007 with Written Opinion for application PCT/US2006/004741. |
PCT International Preliminary Report on Patentability (Chapter I) of Oct. 20, 2009 with Written Opinion of Oct. 3, 2008 for application PCT/US2008/060926. |
PCT International Preliminary Report on Patentability (Chapter I) of Sep. 16, 2005 with Written Opinion of May 9, 2005 for application PCT/US04/007503. |
PCT International Preliminary Report on Patentability (Chapter II) of Apr. 27, 2006 for application PCT/US04/007503. |
PCT International Preliminary Report on Patentability (Chapter II) of Dec. 21, 2006 for application PCT/US2006/002837. |
PCT Search Report of Apr. 6, 2006 and Written Opinion of Apr. 8, 2006 for application PCT/US04/44093. |
PCT Search Report of Aug. 11, 2006 for application PCT/US2006/002837. |
PCT Search Report of Aug. 8, 2006 for appl;ication PCT/US2005/045515. |
PCT Search Report of Dec. 14, 2004 for application PCT/USO4/02856. |
PCT Search Report of Jan. 22, 2009 for application PCT/US2008/80370. |
PCT Search Report of Mar. 25, 2009 for application PCT/US2008/80382. |
PCT Search Report of Oct. 1, 2007 and Written Opinion of Oct. 1, 2007 for application PCT/US07/09499. |
PCT Search Report of Oct. 9, 2008 for application PCT/US2008/060926. |
PCT Written Opinion of Aug. 11, 2006 for application PCT/US2006/002837. |
PCT Written Opinion of Dec. 14, 2004 for application PCT/US04/02856. |
PCT Written Opinion of Dec. 22, 2008 for application PCT/US2008/80370. |
PCT Written Opinion of Mar. 8, 2009 for application PCT/US2008/80382. |
PCT/US2011/026365 International Preliminary Report on Patenability mailed Mar. 5, 2012. |
PCT/US2011/026365 International Written Opinion and Search Report mailed Jul. 13, 2011. |
PCT/US2011/033649 International Written Opinion and Search Report mailed Aug. 26, 2011. |
Peeters et al., "Comparison of four bifunctional reagents for coupling peptides to proteins and the effect of the three moieties on the immunogenicity of the conjugates," J. Immunological Methods, 120:133-143 (1989). |
Perez et al., "The β-Amyloid Precursor Protein of Alzheimer's Disease Enhances Neuron Viability and Modulates Neuronal Polarity," J. Neurosc., 17(24):9407-9414 (1997). |
Persson et al., "IgG subclass-associated affinity differences of specific antibodies in humans," J. Immunology, 140(11):3875-3879 (1988), abstract only. |
Perutz et al., "Amyloid fibers are water-filed nanotubes," PNAS,, 99(8):5591-5595 (2002). |
Peterson, et al., "Recombinant Antibodies: Alternative Strategies for Developing and Manipulating Murine-Derived Monoclonal Antibodies " Laboratory Animal Science, 46(1):8-14 (1996). |
Pfeifer et al., "Cerebral hemorrhage after passive anti-Aβ immunotherapy," Science, 298(5597):1379 (2002). |
Pfizer Announces Co-Primary Clinical Endpoints Not Met in Second Phase 3 Bapineuzumab Study in Mild-to-Moderate Alzheimer's Disease Patients Who Do Not Carry the Apoe4 Genotype, Press Release, Aug. 6, 2012. |
Pfizer Halts Development of AB Antibody, Alzheimer Research Forum, Nov. 2, 2011. |
Pfizer, "Pfizer Announces Topline Results of First of Four Studies in Bapineuzumab Phase 3 Program", Press Release, Jul. 23, 2012. |
Phelps et al., "Development and Characterization of Monoclonal Antibodies Specific for Amylin," Hybridoma, 15(5):379-386 (1996). |
Philippe, et al. "Generation of a monoclonal antibody to the carboxy-terminal domain of tau by immunization with the amino-terminal domain of the amyloid precursor protein," J. of Neuroscience Res., 46:709-719 (1996). |
Piera et al., "Cytokines as adjuvants: effects on the immunogenicity of NeuAc alpha 2-GaINAc alpha-O-Ser/Thr (sialyl-Tn)," Int. J. Cancer 55(1):148-152 (1993). |
Plant et al., "The Production of Amyloid β Peptide is a Critical Requirement for the Viability of Central Neurons," The Journal of Neuroscience, 23(13):5531-5535, (2003). |
Pluckthun, A., "Mono- and Bivalent Antibody Fragments Produced in Escherichia coli: Engineering, Folding and Antigen Binding," Immunological Reviews, 130:151-188 (1992). |
PNAS Information for Authors (revised Jan. 1997), Retrieved Apr. 21, 2008 from http://web.archive.org/web/19970610092808/www.pnas.org/iforc.shtml. |
PNAS instructions for authors, retrieved Oct. 13, 2009 from http://www.pnas.org/site/misc/iforc.shtml#viii. * |
Poduslo et al., "Macromolecular permeability across the blood-nerve and blood-brain barriers." Proc. Natl. Acad. Sci USA. vol. 91 pp. 5705-5709 (1994). |
Poduslo et al., "Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease," Neurobiol. Dis., 8(4):555-567 (2001). |
Prada et al., "Antibody-Mediated Clearance of Amyloid-β Peptide From Cerebral Amyloid Angiopathy Revealed by quantitative in Vivo Imaging," Journal of Neuroscience, 27(8):1973-1980 (2007). |
Press Release, "Alzheimer's vaccine developer awarded Potemkin Prize," American Academy of Neurology, May 1, 2001. |
Prieels et al., "Synergistic adjuvants for vaccines," Chemical Abstracts, 120(8):652, col. 1, abstract 86406t (1994). |
Probert et al., "Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tunmor necrosis factor α," PNAS, 92:11294-11298 (1995). |
Prusiner et al., "Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies," PNAS, 90:10608-10612 (1993). |
Putative CDR determination for SEQ Id Nos. 2 and 4 (pp. 1-2), Jun. 10, 2004. |
Qu et al., "Aβ42 gene Vaccine Prevents Aβ42 deposition in brain of Double Trangenic Mice," J. Neurological Sciences, 260:204-213 (2007). |
Queen et al., "A humanized antibody that binds to the interleukin 2 receptor," PNAS, 86:10029-10033 (1989). |
Quon et al., "Formation of β-Amyloid protein deposits in brains of transgenic mice," Nature, 352:239-241 (1991). |
Raber, et al., "ApoE genotype accounts for the vast majority of AD risk and AD pathology" Neurobiology of Aging, 25:641-650 (2004). |
Racke et al., "Exacerbation of Cerebral Amyloid Angiopathy-Assoiciated Microhemorrhage in Amyloid Precursor Protein Trasngenic Mice by Immunotherapy is Dependent on Antibody Recognition of Deposited Forms of amyloid β," J. Neurosci., 25(3):629-636 (2005). |
Ragusi et al., "Redistribution of Imipramine from Regions of the Brain Under the Influence of Circulating Specific Antibodies," J. Neurochem., 70(5):2099-2105 (1998). |
Rammensee, H.G., "Chemistry of peptides associated with MHC class I and class II molecules," Current Opinion in Immunology, 7:85-96 (1995). |
Ramshaw et al., "DNA vaccines for the treatment of autoimmune disease," Immunology and Cell Biology, 75:409-413 (1997). |
Raso, "Immunotherapy of Alzheimer's Disease," Immunotherapy Weekly, Abstract (Apr. 2, 1998). |
Raso, V.A., Grant application # 1 R43 AGI 5746-01 (non-redacted version), "Immunotherapy of Alzheimer's Disease" (publication date unknown). |
Raso, V.A., Grant application # 1 R43 AGI 5746-01 (redacted version), "Immunotherapy of Alzheimer's Disease" (publication date unknown). |
Ray. "Wyeth Study Finds Alzheimer's Drug Works in ApoE4 Non-Carriers". Poster 2008, [retrieved from the internet 16.06;.2011: <URL: http://elan2006.blogspot.com/2008/07/elan-wyeth-studfindalzheimerdrug.html>]. |
Remes et al., "Hereditary dementia with intracerevbral hemorrhages and cerebral amyloid angiopathy". Neurology 63(2):234-240 (2004). |
Research Corporation Technology News, "THP and SangStat Partner to Develop Humanized Polyclonal Antibody Drugs," Nov. 11, 2002. |
Rieber, et al., "The Effect of Freund's Adjuvants on Blood-Cerebrospinal Fluid Barrier Permeability" Journal of the Neurological Sciences, 63:55-61 (1984). |
Riechmann et al., "Reshaping Human Antibodies for Therapy," Nature, 332:323-327 (1988). |
Rivero et al., "Suppression of experimental autoimmune encephalomyelitis (EAE) by intraperitoneal administration of soluble myelin antigens in Wistar rats" J. Neuroimmunology, (1997) 72, 3-10. |
Robbins et al., "The Intronic Region of an Imcompletely Spliced gp100 Gene Transcript Encodes an Epitope Recognized by Melanoma-Reactive Tumor-Infiltrarting Lymphocytes," Journal of Immunology, 159(1):303-308 (1997). |
Robert et al., Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers:, Protein Eng Des Sel. (2009) 22:(2):199-208. |
Rodriguez et al., "Enfermedad de Azlheimer. Situacion Actual y Estrategias Terapeuticas" (Alzheimer Disease: present situation and therapeutic strategies), Rev Cubana Med [online], 38(2):134-142 (1999). |
Rogers et al., "Complement activation by β-amyloid in Alzheimer Disease," PNAS89:1-5 (1992). |
Roitt, Extracts from Roitt's Essential Immunology, Ninth Edition, (1997). |
Rolph et al., "Recombinant viruses as vaccines and immunological tools," Immunity to Infection, 9:517-521 (1997). |
Rosenberg, R. N., "The Potemkin Prize for Pick's, Alzheimer's Disease and Related Disorders," pp. 1-5. |
Roses, A.D.. "Apoplipoprotein E alleles as risk factors in Alzheimer's disease," Annu. Rev. Med., 47:387-400 (1996). |
Rossor et al., "Alzheimer's Disease Families with Amyloid Precursor Protein Mutations," Annals of New York Academy of Sciences, 695:198-202 (1993). |
Rudikoff et al., "Single amino acid substitution altering antigen-binding specificity," PNAS, 79:1979-1983 (1982). |
Rudinger, "Characteristics of the Amino Acids as Components of a Peptide Hormone Sequence," in Peptide Hormones, J.A. Parson, ed. University Park Press, Baltimore, pp. 1-7 (1976). |
Saido et al., "Amino-and-Carboxyl-Terminal Heterogeneity of β-Amyloid Peptides Deposited in Human Brain," Neuroscience Letters, 215:173-176 (Aug. 8, 1996). |
Saido et al., "Autolytic Transition of μ-Calpain Upon Activation as Resolved by Antibodies Distinguishing Between the Pre- and Post-Autolysis Forms," J. Biochem., 111:81-86 (1992). |
Saido et al., "Spatial Resolution of Fodrin Proteolysis in Postischemic Brain," J. Biol. Chem., 268(33):25239-25243 (1993). |
Saido et al., "Spatial Resolution of the Primary β-Amyloidogenic Process Induced in Postischemic Hippocampus " J. Biol. Chem., 269(21):15253-15257 (1994). |
Saito et al., "Vector-mediated delivery of 125I-labeled β-amyloid peptide Ab1-40through the blood-brain barrier and binding to Alzheimer disease amyloid of the Aβ vector complex," PNAS, 92:10227-10231 (1995). |
Saitoh, N. et al., "Immunological analysis of Alzheimer's disease using anti- β-protein monoclonal antibodies," Sapporo Med. J., 60:309-320 (1991). |
Saldanha et al., "A single backmutation in the human kIV framework of a previously unsuccessfully humanized antibody restores the binding activity and increases the secretion in cos cells, " Molecular Immunology, 36:709-719 (1999). |
Sasaki•et al, "Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemidal, immunohistochemical and ultrastructural study," Brain Res., 755:193-201 (1997). |
Schenk et al."Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse," Nature, 400:173-177 (1999). |
Schenk et al., "Current progress in beta-amyloid immunotherapy," Curr. Opin. Immunology, 16(5):599-606 (2004). |
Schenk et al., "Immunotherapy with beta-amyloid for Alzheimer's disease: a new frontier," DNA Cell Biol., 20(11):679-81 (2001). |
Schenk et al., "Therapeutic Approaches Related to Amyloid-62 Peptide and Alzheimer's Disease," J. Med. Chem., 38(21):4141-4154 (1995). |
Schenk et al.; "β-peptide immunization," Arch. Neurol., 57:934-936 (2000). |
Schenk, D., "Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning " Nature Reviews, 3:824-828 (2002). |
Schmid, R. E., "Study suggest Alzheimer vaccine fix," from www.msnbc.com/news, pp. 1-5 (2002). |
Schmidt et al., "Monoclonal Antibodies to a 100-kd protein reveal abundant A beta-negative plaques throughout gray matter of Alzheimer's disease brains," The American Journal of Pathology, 1(151):69-80 (1997). |
Schmitt et al., "Interactions of the alzheimer β amyloid fragment(25-35) with peripheral blood dendritic cells," Mechanisms of Ageing and Development, 94:223-232 (1997). |
Schroeder et al. (Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci U S A. Aug. 1990;87(16):6146-50). * |
Schroeder et al. Immunoglobulin heavy chain [Homo sapiens]. GenBank accession No. AAA69734. Jul. 11, 1995. * |
Schroeder et al., "Preferential Utilization of Conserved Immunoglobulin Heavy Chain Variable Gene Segments During Human Fetal Life," Immunology, 87:6146-6150 (1990). |
Schwarzman et al., "Transthyretin sequesters amyloid β protein and prevents amyloid formation," PNAS, 91:8368-8372 (1994). |
Seabrook et al., "Species-specific Immune response to Immunization with Human Versus rodent Abeta Peptide," Neuobiology of Aging, 25(9) 1141-1151 (2004). |
Seidl et al., "Predominant VH genes expressed in innate antibodies are associated with distinctive antigen-binding sites," PNAS, 96:2262-2267 (1999). |
Sela et al, "Different roles of D-amino acids in immune phenomena," FASEB J, 11(6):449-456 (1999) . . . . |
Selkoe, "Alzheimer's Disease: A Central Role for Amyloid," J. Neuropathol. Exp. Neurol., 53(5): 438-447 (1994). |
Selkoe, "Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease," Trends in Neurosciences, 16(10): 403-409 (1993). |
Selkoe, "The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease," Trends Cell Biol., 8(11):447-53 (1998). |
Selkoe, D. J., "Alzheimer's disease is a synaptic failure," Science, 298(5594):789-791 (2002). |
Selkoe, D.J., "Imaging Alzheimer's Amyloid," Nat. Biotech., 18:823-824 (2000). |
Selkoe, Dennis J., "Alzheimer's Disease: Genotypes, Phenotype, and Treatments," Science, 275:630-631 (1997). |
Selkoe, Dennis J., "Amyloid Protein and Alzheimer's Disease . . . ," Scientific American, pp. 68-78 (1991). |
Selkoe, Dennis J., "In the Beginning . . . ," Nature, 354:432-433 (1991). |
Sergeant et al., "Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach," J. Neurochem., 85(6):1581-1591 (2003). |
Servillo, et al., "Posterior reversible encphalopathy syndrome in intensive care medicine" Intensive Care Med, (2007) 33:230-236. |
Seubert et al., "Antibody Capture of Soluble Aβ does not Reduce Cortical Aβ Amyloidosis in the PDAPP Mouse," Neurodegenerative Diseases, (2007). |
Seubert et al., "Antibody Capture of Soluble Aβ does not Reduce Cortical Aβ Amyloidosis in the PDAPP Mouse," Neurodegenerative Diseases, 5:65-71 (2008). |
Seubert et al., "Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids," Nature 359: 325-327 (1992). |
Sheehan et al., "The Utilization of Individual VH Exons in the Primary Repertoire of Adult BALB/c Mice1," The Journal of Immunology, 151(10):5364-5375 (Nov. 15, 1993). |
Shepherd et al., "The design of the humanized antibody," Monocolonal Antibodies: A Pratical Approcach 58-66 (2000). |
Shinkai et al., "Amyloid β-Proteins 1-40 and 1-42(43) in the Soluble Fraction of Extra- and Intracranial Blood Vessels," Ann. Neurol., 38:421-428 (1995). |
Shiosaka, S., "Attempts to make models for Alzheimer's disease," Neuroscience Res. 13:237-255 (1992). |
Sidhu, "p. display in pharmaceutical biotechnology," Current Opinoin in Biotechnology., 11:610-616 (2000). |
Sigmund, "Viewpoint: Are Studies in Genetically Altered Mice Out of Control,"Arterioscler Thromb Vasc Biol., 20:1425-1429 (2000). |
Signet Laboratories, Inc., Product data sheet for mouse monoclonal done 6E10, revised Jul. 13, 2005. |
Sigurdsson et al., "A safer vaccine for Alzheimer's disease?," Neurobiology of Aging 23:1001-1008 (2002). |
Sigurdsson et al., "Anti-priori antibodies for prophylaxis following prion exposure in mice," Neurosciences Letters, 336:185-187 (2003). |
Sigurdsson et al., "Immunization Delays the Onset of Prion Disease in Mice," American Journal of Pathology, 161:13-17 (2002). |
Sigurdsson et al., "Immunization with a Nontoxic/Nonfibrillar Amyloid-β Homologous Peptide Reduces Alzheimer's Disease-Associated Pathology in Trasngenic Mice," Am. J. Pathology, 159(2):439-447 (2001). |
Sigurdsson, et al., "in vivo reversal of amyloid-beta lesions in rat brain," J Neuropathol Exp Neurol., 59(1):11-17 (2000). |
Simmons, L., "Secondary structure of amyloid β peptide correlates with neurotoxic activity in vitro," Molecular Pharmacology, 45:373-379 (1994). |
Singh, K. S., "Neuroautoimmunity: Pathogenic Implications for Alzheimer's Disease," Gerontology, 43:79-94 (1997). |
Singh, V. K., "Studies of neuroimmune markers in Alzheimer's disease," Mol. Neurobiology, 9(1-3):73-81 (1994), abstract only. |
Sinha, et al., "Recent advances in the understanding of the processing of APP to beta amyloid peptide," Ann N Y Aced Sci., 920:206-8 (2000). |
Sipe, "Amyloidosis," Annu. Rev. Biochem., 61:947-975 (1992). |
Skolnick and Fetrow, "From genes to protein structure and function: novel applications of computational approaches in the genomic era " Trends in Biotech, 18(1):34-39 (2000). |
Small et al., "Alzheimer's disease and Abeta toxicity: from top to bottom," Nat Rev Neurosci.,.2(8):595-598 (2001). |
Small et al., "Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease," PNAS, 97(11):6037-6042 (2000). |
Small, " the Role of the Amyloid Protien Precursors (APP) in Alzheimer's Disease: Does the Normal Function of APP Explain the Topography of Neurodegeneration?," Neurochemical Research, 23(5):795-806 (1997). |
Smith et al., "Phage Display," Chemical Reviews, American Chemical Society, 97(2):391-410 (1997). |
Smith et al., "The challenges of genome sequence annotation or ‘The devil is in the details,’" Nature Biotechnology, 15:1222-1223 (1997). |
Smith, et al., "Use of structural inaging to study the progression of Alzheimer's disease", Brit. Med. Bull., 52(3):575-586, (1996). |
Smits et al., "Prion Protein and Scrapie Susceptibility," Vet. Quart., 19(3):101-105 (1997). |
Solomon and et al., "Modulation of the Catalytic Pathway of Carboxypeptidase A by Conjugation with Polyvinyl Alcohols," Adv. Mol. Cell Biology, 15A:33-45 (1996). |
Solomon et al., "Activity of monoclonal antibodies in prevention of in vitro aggregation of their antigens," abstract from Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel (publication date unknown). |
Solomon et al., "Activity of monoclonal antibodies in prevention of in vitro aggregation of their antigens," Immunotechnology, 2(4):305 (1996). |
Solomon et al., "Disaggregation of Alzheimer β-amyloid by site-directed mAb," PNAS94:4109-4112 (1997). |
Solomon et al., "Fast induction of anti-β-amyloid peptide immune response," Research and Practice in Alzheimer's Disease, 6:260-264 (2002). |
Solomon et al., "Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer β- amyloid peptide," PNAS, 93:452-455 (1996). |
Solomon et al., "The Amino Terminus of the β-Amyloid Peptide Contains an Essential Epitope for Maintaining Its Solubility," from Progress in Alzheimer's and Parkinson's Diseases, edited by Fisher et al., Plenum Press, New York, pp. 205-211 (1995). |
Solomon, "Alzheimer's Disease and Immunotherapy", Current Alzheimer Research, 2004, 1, 149-163. |
Solomon, "Beta-Amyloid-Based Immunotherapy as a Treatment of Alzheimer's Disease", Drugs of Today, 2007, 43(5):333-342. |
Solomon, A., "Pro-Rx (Protein Therapeutics)," University of Tennessee Medical Center (publication date unknown). |
Solomon, B., "Generation and brain delivery of anti-aggregating antibodies against b-amyloid plaques using phage display technology," J. Neural Transm. Suppl., 62:321-325 (2002). |
Solomon, B., "Immunological approaches as therapy for Alzheimer's disease " Expert Opin. Biol. Ther., 2(8):907-917 (2002). |
Solomon, B., "Immunotherapeutic strategies for prevention and treatment of Alzheimers disease," DNA and Cell Biology, 20(11):697-703 (2001). |
Solomon, B., "New Approach Towards Fast Induction of Anti β-Amyloid Peptide Immune Response," Department of Molecular Microbiology & Biotechnology, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel (publication date unknown). |
Sood et al., "Synthetic Peptides: A Modern Approach to Vaccination," Indian Journal of Experimental Biology, 34:849-861 (1998). |
Soto et al., "Beta sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy," Nature Medicine., 4(7):822-826 (1998). |
Soto et al., "The conformation of Alzheimer's beta peptide determines the rate of amyloid formation and its resistance to proteolysis," Biochem. J ., 314:701-707 (1996). |
Soto et al., "The α-helical to β-strand transition in the amino-terminal fragment of the amyloid β- peptide modulates amyloid formation," J. Biol. Chem, 270(7):3063-3067 (1995). |
Souder et al., "Overview of Alzheimer's disease," Nurs. Clin. N. Am., 39:545-559 (2004). |
Southwick et al., "Assessment of Amyloid β protein in Cerebrospinal fluid as an Aid in the Diagnosis of Alzheimer's Disease," J. Neurochemistry, 66:259-265 (1996). |
Spack, "Antigen-specific therapies for the treatment of multiple sclerosis: a clinical trial update", Exp. Opin. Invest. Drugs, (1997) 6(11):1715-1727. |
Spellerberg et al., "DNA Vaccines Against Lymphoma," Journal of Immunology, 159:1885-1892 (1997). |
Sperling, et al., "Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup" Alzheimer's & Dementia, 7 (2011) 397-385. |
Sperling, et al., Presentation and Transcript of "Bapineuzumab Phase 3 trials in mild to moderate Alzheimer's disease dementia in apolipoprotein E ε4 carriers (Study 302) and non-carriers (Study 301)", American Neurological Association, Oct. 8, 2012. |
Spooner et al., "The generation and characterization of potentially therapeutic Aβ antibodies in mice: differences according to strain and immunization protocol " Vaccine, 21:290-297 (2002). |
St. George-Hyslop et al., "Antibody clears senile plaques," Nature, 40:116-117 (1999). |
Staunton et al., "Primary structures of ICAM-1 demonstrates interaction between members of the immunoglobulin and intergrin supergene families," Cell 52(6):925-33 (1988), abstract only. |
Staykov, et al., "Posterior Reversible Encephalopathy Syndrome", Journal of Intensive Care Medicine, originally published online Jan. 21, 2011 at: http://jic.sagepub.com/content/27/1/11. |
Stedman's Medical Dictionary, 27th Edition, "Vaccine," p. 1922, lines 1-3 (2000). |
Stein et al., "Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein is Associated with Increased Levels of Transthyretin and Activation of Cell Survival Pathways," The Journal of Neuroscience, 22(17):7380-7388 (2002). |
Stern et al., "Antibodies to the β-amyloid peptide cross-react with conformational epitopes in human fibrinogen subunits from peripheral blood," FEBS Letters264(1):43-47 (1990). |
Stern, et al. "Monoclonal Antibodies to a Synthetic Peptide Homologous with the First 28 Amino Acids of Alzheimer's Disease β-Protein Recognize Amyloid and Diverse Glial and Neuronal Cell Types in the Central Nervous System" Am J of Pathology, 134(5):973-978 (1989). |
Stoute et al., "A Preliminary Evaluation of a Recombinant Circumsporozoite Protein Vaccine Against Plasmodium falciparum Malaria", N. Emil. J. Med., 336(2):86-91 (1997). |
Strbak et al., "Passive Immunization and Hypothalamic Peptide Secretion" Neuroendocrinolog, 58:210-217 (1993). |
Studnicka et al., "Human-engineered monocilnal antibodies retain full specific binding activity by preserving non-CDR complemenatary-modullating resudes," Protien Eng., 7(6):805-814 (1994), Abstract only. |
Sturchler-Pierrat et al., "Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology," PNAS, 94: 13287-13292 (1997). |
Su et al., "Intravascular infusions of soluble β-amyloid compromise the blood-brain barrier, activate CNS Glial cells and induce peripheral hemorrhage," Brain Research, 818:105-107 (1999). |
Suo et al., "Soluble Alzhelmers β-amyloid constricts the cerebral vasculature in vivo" Neurscience Letters, 257:77-80 (1998). |
Supplementary Partial European Search Report of Apr. 10, 2007 for European Application 04720353.4-1222. |
Sussex Drug Discovery, "Bexarontene in Alzheimer's Disease: A case of lack of replication, lace of replication, lack of replication," Retrieved from the Internet http://sussexdrugdiscover.wordpress.com/tag/bapineuzumab, pp. 1-4 (retrieved on Sep. 27, 2013) Jun. 20, 2013. |
Szendrei, et al., "The effects of aspartic acid-bond isomerization on in vitro properties of the amyloid β-peptide as modeled with N-terminal decapeptide fragments," Int. J. Peptide Protein Res., 47:289-296 (1996). |
Tabaton et al., "Soluble amyloid β-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid," Biochem. and Biophys. Res. Comm., 200(3)1598-1603 (1994). |
Tahtinen et al., "Minimal Size of HIV-1 NEF Antigenic Epitopes Reconzied by Human Sera," Int. Conf. AIDS Jun. 16-21 1991, Published Jun. 1991, abstract No.. W.A. 1334. |
Takahashi, et al. "Monoclonal antibody to β peptide, recognizing amyloid deposits, neuronal cells and lipofuscin pigments in systemic organs", Acta Neuropathol, 85:159-166 (1993). |
Tal et al., "Complete Freund's Adjuvant Immunization Prolongs Survival in Experimental Prion Disease in Mice," Journal of Neuroscience Research, 71:286-290 (2003). |
Tam, "Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system", Proc. Natl. Acad. Sci., 1988, vol. 85, pp. 5409-5413. |
Tamaokaet al., "Antibodies to amyloid beta protein (A beta) crossreact with glyceraldehyde-3-phosphate dehyrogenase (GAPDH)," Neurobiology of Aging, 3(17):405-414 (1996). |
Tan et al., "Amyloidosis," Histopathology, 25:403-414 (1994). |
Tanaka et al., "NC-1900, an active fragment analog of arginine vasopressin, improves learning and memory deficits induced by beta-amyloid protein in rats," European J. Pharmacology, 352:135-142. |
Tang et al., "Genetic immunization is a siple method for eliciting an immune response," Nature, 356:152-154 (1992). |
Teller et al., "Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down's syndrome" Nature Medicine, 2(1):93-95 (1996). |
Tennent et al., "Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer's disease and systemic amyloidosis," PNAS, 92:4299-4303 (1995). |
Thompson, et al., "Laboratory investigation of cerebrospinal fluid proteins" Ann Clin Biochem, 27:425-435 (1990). |
Thorsett, E.D. et al., "Therapeutic approaches to Alzheimer's disease," Curr. Op. in Chem. Biology4:377-382 (2000). |
Tjernberg et al., "A molecular model for Alzheimer amyloid β-peptide fibril formation," J. Biol. Chem., 274(18):12619-12625 (1999). |
Tjernberg et al., "Arrest of β-amyloid fibril formation by a pentapeptide ligand," J. Biol. Chem., 271:8545-8548 (1996). |
Tjernberg, et al, "Controlling amyloid beta-peptide fibril formation with protease-stable ligands," J. Biol Chem., 272(19):12601-12605 (1997). |
Town et al., "Characterization of murine immunoglobulin G antibodies against human amyloid-β1-42" Neurosci. Lett, 307:101-104 (2001). |
Trang et al., "Pharmacokinetics of a Mouse/Human Chimeric Monoclonal Antibody (C-17-1A) in Metastatic Adencarcinoma Patients," Pharmacutical Research 7(6):587-592 (1990). |
Travis, J., "A Vaccine for Alzheimer's Disease?®," Science News Online, 156(2) pp. 1-3 downloaded from Internet (1999). |
Travis, J., "Saving the Mind Faces High Hurdles," Science, 309:731-734 (2005). |
Trieb et al., "APP Peptides Stimulate Lymphocyte Proliferation in Normals, But Not in Patients With Alzheimer's Disease," Neurobiology of Aging, 17(4):541-547 (1996). |
Trieb et al., "Is Alzheimer beta amyloid precursor protein (APP) an autoantigen? Peptides corresponding to parts of the APP sequence stimulate T lymphocytes in normals, but not in patients with Alzheimer's disease," Immunobiology, 191(2-3):114-115 Abstract C.37, (1994). |
Triguero, et al., "Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein" Proc. Natl. Acad. Sci. USA, vol. 86:4761-4765 Jun. 1989. |
Triozzi et al., "Effects of a beta-human chorionic gonadotropin subunit immunogen administered in aqueous solution with a novel nonionic block copolymer adjuvant in patients with advanced cancer", Clin. Cancer Res., (1997) 3(12 pt 1):2355-2362 (abstract only). |
Trojano, et al., "Serum IgG to brain microvascular endothelial cells in multiple sclerosis" Journal of the Neurological Sciences, 143:107-113 (1996). |
Tsuzuki et al., "Amyloid β protein in rat soleus in choroquine-induced myopthy using end-specific antibodies for Aβ4O and Aβ42: immunohistochemical evidence for amyloid β protein " Neuroscience Letters, 2002:77-80 (1995). |
Tuomanen, et al., "Reversible opening of the blood-brain barrier by anti-bacterial antibodies" Proc. Natl. Acad. Sci. USA, vol. 90:7824-7828 (Aug. 1993). |
U.S. Appl. No. 09/201,430, Advisory Action mailed Jun. 18, 2002. |
U.S. Appl. No. 09/201,430, Examiner Interview Summary mailed May 30, 2001. |
U.S. Appl. No. 09/201,430, Office Action mailed Dec. 21, 1999. |
U.S. Appl. No. 09/201,430, Office Action mailed Jan. 17, 2001. |
U.S. Appl. No. 09/201,430, Office Action mailed May 10, 2000. |
U.S. Appl. No. 09/201,430, Office Action mailed Nov. 26, 2001. |
U.S. Appl. No. 09/201,430, Office Action mailed Oct. 1, 2002. |
U.S. Appl. No. 09/204,838, filed Dec. 3, 1998, Weiner. |
U.S. Appl. No. 09/204,838, Office Action mailed Apr. 18, 2003. |
U.S. Appl. No. 09/204,838, Office Action mailed Dec. 21, 2000. |
U.S. Appl. No. 09/204,838, Office Action mailed Mar. 17, 2000. |
U.S. Appl. No. 09/204,838, Office Action mailed Sep. 27, 2001. |
U.S. Appl. No. 09/316,387, Declaration of Solomon, Hrncic, and Wall under 37 C.F.R. § 1.131 filed Mar. 6, 2006. |
U.S. Appl. No. 09/316,387, Office Action mailed Jun. 20, 2005. |
U.S. Appl. No. 09/316,387, Office Action mailed Sep. 10, 2007. |
U.S. Appl. No. 09/316,387, Response to Jun. 20, 2005 Office Action filed Dec. 20, 2005. |
U.S. Appl. No. 09/322,289, Examiner Interview Summary mailed Jan. 15, 2009. |
U.S. Appl. No. 09/322,289, Examiner Interview Summary mailed Jun. 27, 2006. |
U.S. Appl. No. 09/322,289, filed May 28, 1999, Schenk. |
U.S. Appl. No. 09/322,289, Office Action mailed Feb. 24, 2005. |
U.S. Appl. No. 09/322,289, Office Action mailed Feb. 7, 2008. |
U.S. Appl. No. 09/322,289, Office Action mailed Jul. 17, 2007. |
U.S. Appl. No. 09/322,289, Office Action mailed Jun. 19, 2001. |
U.S. Appl. No. 09/322,289, Office Action mailed Jun. 4, 2009. |
U.S. Appl. No. 09/322,289, Office Action mailed Nov. 17, 2006. |
U.S. Appl. No. 09/322,289, Office Action mailed Nov. 29, 2005. |
U.S. Appl. No. 09/322,289, Office Action mailed Nov. 4, 2008. |
U.S. Appl. No. 09/322,289, Office Action mailed Oct. 16, 2005. |
U.S. Appl. No. 09/322,289, Office Action mailed Sep. 29, 2000. |
U.S. Appl. No. 09/441,140, filed Nov. 16, 1999, Solomon et al. |
U.S. Appl. No. 09/497,553, filed Feb. 3, 2000, Schenk. |
U.S. Appl. No. 09/497,553, Office Action mailed Nov. 29, 2005. |
U.S. Appl. No. 09/497,553, Office Action mailed Oct. 3, 2003. |
U.S. Appl. No. 09/579,690, filed May 26, 2000, Brayden. |
U.S. Appl. No. 09/580,015, filed May 26, 2000, Schenk. |
U.S. Appl. No. 09/580,015, Office Action mailed Feb. 11, 2002. |
U.S. Appl. No. 09/580,018, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/580,018, Office Action mailed May 20, 2003. |
U.S. Appl. No. 09/580,019, filed May 26, 2000, Schenk. |
U.S. Appl. No. 09/580,019, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/585,656. |
U.S. Appl. No. 09/723,313, Office Action mailed Mar. 26, 2002. |
U.S. Appl. No. 09/723,384, Examiner Interview Summary mailed Mar. 28, 2003. |
U.S. Appl. No. 09/723,384, Office Action mailed Oct. 9, 2002. |
U.S. Appl. No. 09/723,544, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/723,544, Office Action mailed Aug. 11, 2003. |
U.S. Appl. No. 09/723,544, Office Action mailed Sep. 23, 2002. |
U.S. Appl. No. 09/723,713, Advisory Action mailed Dec. 20, 2004. |
U.S. Appl. No. 09/723,713, filed Nov. 27, 2000, Schenk. |
U.S. Appl. No. 09/723,713, Office Action mailed Apr. 19, 2005. |
U.S. Appl. No. 09/723,713, Office Action mailed Feb. 12, 2002. |
U.S. Appl. No. 09/723,713, Office Action mailed Jan. 11, 2006. |
U.S. Appl. No. 09/723,713, Office Action mailed Jun. 3, 2004. |
U.S. Appl. No. 09/723,713, Office Action mailed Oct. 24, 2003. |
U.S. Appl. No. 09/723,725, filed Nov. 27, 2000, Hirtzer. |
U.S. Appl. No. 09/723,725, Office Action mailed Dec. 9, 2002. |
U.S. Appl. No. 09/723,760, Advisory Action mailed Dec. 16, 2004. |
U.S. Appl. No. 09/723,760, filed Nov. 27, 2000, Schenk. |
U.S. Appl. No. 09/723,760, Office Action mailed Dec. 19, 2002. |
U.S. Appl. No. 09/723,760, Office Action mailed Dec. 29, 2005. |
U.S. Appl. No. 09/723,760, Office Action mailed Feb. 23, 2004. |
U.S. Appl. No. 09/723,760, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/723,760, Office Action mailed May 4, 2005. |
U.S. Appl. No. 09/723,762, Office Action mailed Oct. 2, 2001. |
U.S. Appl. No. 09/723,765, Advisory Action mailed Feb. 9, 2004. |
U.S. Appl. No. 09/723,765, BPAI Decision on Request for Re-Hearing mailed Oct. 16, 2007. |
U.S. Appl. No. 09/723,765, BPAI Order Returning Appeal to Examiner mailed Jun. 27, 2006. |
U.S. Appl. No. 09/723,765, Examiner Interview Summary mailed Jan. 16, 2009. |
U.S. Appl. No. 09/723,765, Examiner Interview Summary mailed Jan. 25, 2006. |
U.S. Appl. No. 09/723,765, Examiner Interview Summary mailed Mar. 18, 2003. |
U.S. Appl. No. 09/723,765, Examiner Interview Summary mailed Oct. 8, 2008. |
U.S. Appl. No. 09/723,765, Examiner's Answer mailed Jan. 25, 2006. |
U.S. Appl. No. 09/723,765, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/723,765, Office Action mailed Aug. 10, 2004. |
U.S. Appl. No. 09/723,765, Office Action mailed Dec. 3, 2002. |
U.S. Appl. No. 09/723,765, Office Action mailed Dec. 5, 2008. |
U.S. Appl. No. 09/723,765, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/723,765, Office Action mailed May 22, 2008. |
U.S. Appl. No. 09/723,765, Office Action mailed May 4, 2005. |
U.S. Appl. No. 09/723,765, Office Action mailed Oct. 22, 2008. |
U.S. Appl. No. 09/723,765, Office Action mailed Oct. 7, 2003. |
U.S. Appl. No. 09/723,765, Reply Brief Noted mailed Jun. 16, 2006. |
U.S. Appl. No. 09/723,766, filed Nov. 27, 2000, Hirtzer. |
U.S. Appl. No. 09/723,766, Office Action mailed Jun. 11, 2002. |
U.S. Appl. No. 09/723,766, Office Action mailed Mar. 5, 2002. |
U.S. Appl. No. 09/723,766, Office Action mailed Nov. 1, 2002. |
U.S. Appl. No. 09/724,102, Office Action mailed Oct. 3, 2001. |
U.S. Appl. No. 09/724,273, Advisory Action mailed Jun. 16, 2005. |
U.S. Appl. No. 09/724,273, Advisory Action mailed Mar. 18, 2004. |
U.S. Appl. No. 09/724,273, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/724,273, Office Action mailed Apr. 21, 2003. |
U.S. Appl. No. 09/724,273, Office Action mailed Aug. 22, 2007. |
U.S. Appl. No. 09/724,273, Office Action mailed Dec. 22, 2006. |
U.S. Appl. No. 09/724,273, Office Action mailed Dec. 28, 2004. |
U.S. Appl. No. 09/724,273, Office Action mailed Jul. 2, 2002. |
U.S. Appl. No. 09/724,273, Office Action mailed Jun. 22, 2004. |
U.S. Appl. No. 09/724,273, Office Action mailed Jun. 8, 2006. |
U.S. Appl. No. 09/724,273, Office Action mailed Nov. 8, 2005. |
U.S. Appl. No. 09/724,273, Office Action mailed Oct. 16, 2003. |
U.S. Appl. No. 09/724,288, Advisory Action mailed Jan. 6, 2004. |
U.S. Appl. No. 09/724,288, Advisory Action mailed Mar. 3, 2006. |
U.S. Appl. No. 09/724,288, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/724,288, Office Action mailed Apr. 23, 2007. |
U.S. Appl. No. 09/724,288, Office Action mailed Dec. 11, 2002. |
U.S. Appl. No. 09/724,288, Office Action mailed Dec. 14, 2004. |
U.S. Appl. No. 09/724,288, Office Action mailed Dec. 22, 2008. |
U.S. Appl. No. 09/724,288, Office Action mailed Jul. 12, 2005. |
U.S. Appl. No. 09/724,288, Office Action mailed Jun. 21, 2006. |
U.S. Appl. No. 09/724,288, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/724,288, Office Action mailed Mar. 18, 2008. |
U.S. Appl. No. 09/724,288, Office Action mailed May 3, 2004. |
U.S. Appl. No. 09/724,288, Office Action mailed Oct. 3, 2007. |
U.S. Appl. No. 09/724,288, Office Action mailed Sep. 9, 2003. |
U.S. Appl. No. 09/724,291, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/724,319 Office Action mailed May 2, 2006. |
U.S. Appl. No. 09/724,319, Examiner Interview Summary mailed Apr. 9, 2008. |
U.S. Appl. No. 09/724,319, Examiner Interview Summary mailed Jul. 19, 2004. |
U.S. Appl. No. 09/724,319, filed Nov. 27, 2000, Schenk. |
U.S. Appl. No. 09/724,319, Office Action mailed Apr. 26, 2004. |
U.S. Appl. No. 09/724,319, Office Action mailed Apr. 8, 2009. |
U.S. Appl. No. 09/724,319, Office Action mailed Aug. 15, 2005. |
U.S. Appl. No. 09/724,319, Office Action mailed Jan. 11, 2008. |
U.S. Appl. No. 09/724,319, Office Action mailed Jul. 21, 2003. |
U.S. Appl. No. 09/724,319, Office Action mailed May 16, 2007. |
U.S. Appl. No. 09/724,477, Office Action mailed Oct. 2, 2001. |
U.S. Appl. No. 09/724,489, Office Action mailed Oct. 2, 2002. |
U.S. Appl. No. 09/724,495, Advisory Action mailed May 16, 2004. |
U.S. Appl. No. 09/724,495, filed Nov. 27, 2000, Schenk. |
U.S. Appl. No. 09/724,495, Office Action mailed Jan. 16, 2004. |
U.S. Appl. No. 09/724,495, Office Action mailed Mar. 13, 2003. |
U.S. Appl. No. 09/724,495, Office Action mailed Sep. 24, 2002. |
U.S. Appl. No. 09/724,495, Office Action mailed Sep. 26, 2005. |
U.S. Appl. No. 09/724,551, Office Action mailed Jul. 2, 2002. |
U.S. Appl. No. 09/724,551, Office Action mailed Jun. 3, 2003. |
U.S. Appl. No. 09/724,552, Examiner Interview Summary mailed Dec. 3, 2003. |
U.S. Appl. No. 09/724,552, Office Action mailed Jun. 3, 2003. |
U.S. Appl. No. 09/724,552, Office Action mailed May 6, 2002. |
U.S. Appl. No. 09/724,567, Office Action mailed Jul. 23, 2003. |
U.S. Appl. No. 09/724,567, Office Action mailed Mar. 27, 2002. |
U.S. Appl. No. 09/724,567, Office Action mailed Nov. 15, 2002. |
U.S. Appl. No. 09/724,575, Advisory Action mailed Feb. 12, 2004. |
U.S. Appl. No. 09/724,575, Examiner Interview Summary mailed May 6, 2005. |
U.S. Appl. No. 09/724,575, filed Nov. 28, 2000, Schenk. |
U.S. Appl. No. 09/724,575, Office Action mailed Jul. 25, 2003. |
U.S. Appl. No. 09/724,575, Office Action mailed Mar. 27, 2002. |
U.S. Appl. No. 09/724,575, Office Action mailed Mar. 31, 2006. |
U.S. Appl. No. 09/724,575, Office Action mailed May 6, 2005. |
U.S. Appl. No. 09/724,575, Office Action mailed Nov. 21, 2002. |
U.S. Appl. No. 09/724,575, Office Action mailed Oct. 12, 2006. |
U.S. Appl. No. 09/724,575, Office Action mailed Oct. 17, 2005. |
U.S. Appl. No. 09/724,842, filed Nov. 28, 2000, Chalifour et al. |
U.S. Appl. No. 09/724,921, filed Nov. 28, 2000, Weiner. |
U.S. Appl. No. 09/724,921, Office Action mailed Apr. 30, 2002. |
U.S. Appl. No. 09/724,921, Office Action mailed Jan. 28, 2003. |
U.S. Appl. No. 09/724,929, filed Nov. 28, 2000, Weiner. |
U.S. Appl. No. 09/724,929, Office Action mailed Jul. 22, 2003. |
U.S. Appl. No. 09/724,929, Office Action mailed Mar. 22, 2002. |
U.S. Appl. No. 09/724,940, Office Action mailed Dec. 24, 2003. |
U.S. Appl. No. 09/724,940, Office Action mailed Mar. 13, 2003. |
U.S. Appl. No. 09/724,953, Office Action mailed Jul. 25, 2003. |
U.S. Appl. No. 09/724,953, Office Action mailed Mar. 26, 2002. |
U.S. Appl. No. 09/724,953, Office Action mailed Nov. 27, 2002. |
U.S. Appl. No. 09/724,961, Examiner Interview Summary mailed Dec. 3, 2003. |
U.S. Appl. No. 09/724,961, Office Action mailed Mar. 12, 2002. |
U.S. Appl. No. 09/724,961, Office Action mailed May 16, 2003. |
U.S. Appl. No. 09/979,701, filed Mar. 13, 2002, Schenk. |
U.S. Appl. No. 09/979,701, Office Action mailed Feb. 15, 2005. |
U.S. Appl. No. 09/979,701, Office Action mailed Jan. 10, 2006. |
U.S. Appl. No. 09/979,701, Office Action mailed Sep. 15, 2005. |
U.S. Appl. No. 09/979,952, Office Action mailed Aug. 7, 2003. |
U.S. Appl. No. 09/979,952, Office Action mailed Dec. 30, 2003. |
U.S. Appl. No. 09/980,568, filed Mar. 12, 2005, Hirtzer. |
U.S. Appl. No. 09/980,568, Office Action mailed Feb. 23, 2004. |
U.S. Appl. No. 09/980,568, Office Action mailed May 29, 2003. |
U.S. Appl. No. 09/980,568, Office Action mailed Nov. 2, 2004. |
U.S. Appl. No. 10/010,942, Examiner Interview Summary mailed Feb. 22, 2006. |
U.S. Appl. No. 10/010,942, Examiner Interview Summary mailed Jan. 19, 2005. |
U.S. Appl. No. 10/010,942, Examiner Interview Summary mailed May 10, 2006. |
U.S. Appl. No. 10/010,942, Examiner Interview Summary mailed May 11, 2006. |
U.S. Appl. No. 10/010,942, Examiner Interview Summary mailed Nov. 18, 2004. |
U.S. Appl. No. 10/010,942, Office Action mailed Jan. 19, 2005. |
U.S. Appl. No. 10/010,942, Office Action mailed May 26, 2004. |
U.S. Appl. No. 10/010,942, Office Action mailed Oct. 3, 2005. |
U.S. Appl. No. 10/010,942, Office Action mailed Sep. 24, 2003. |
U.S. Appl. No. 10/230,030, Examiner Interview Summary mailed Feb. 17, 2006. |
U.S. Appl. No. 10/232,030, Advisory Action mailed Oct. 30, 2006. |
U.S. Appl. No. 10/232,030, Office Action mailed Apr. 1, 2008. |
U.S. Appl. No. 10/232,030, Office Action mailed Dec. 2, 2004. |
U.S. Appl. No. 10/232,030, Office Action mailed Jun. 15, 2007. |
U.S. Appl. No. 10/232,030, Office Action mailed Oct. 14, 2005. |
U.S. Appl. No. 10/388,214, Examiner Interview Summary mailed Nov. 6, 2006. |
U.S. Appl. No. 10/388,214, Examiner Interview Summary mailed Oct. 2, 2006. |
U.S. Appl. No. 10/388,214, Office Action mailed Jan. 31, 2006. |
U.S. Appl. No. 10/388,214, Office Action mailed Jul. 28, 2006. |
U.S. Appl. No. 10/388,214, Office Action mailed May 31, 2005. |
U.S. Appl. No. 10/388,389, Examiner Interview Summary mailed May 22, 2006. |
U.S. Appl. No. 10/388,389, Examiner Interview Summary mailed May 31, 2006. |
U.S. Appl. No. 10/388,389, Office Action mailed Nov. 22, 2005. |
U.S. Appl. No. 10/429,216, Examiner Interview Summary mailed Mar. 6, 2006. |
U.S. Appl. No. 10/429,216, Office Action mailed Apr. 11, 2006. |
U.S. Appl. No. 10/429,216, Office Action mailed Dec. 28, 2005. |
U.S. Appl. No. 10/429,216, Office Action mailed Jan. 28, 2008. |
U.S. Appl. No. 10/429,216, Office Action mailed Mar. 12, 2010. |
U.S. Appl. No. 10/429,216, Office Action mailed Mar. 6, 2009. |
U.S. Appl. No. 10/429,216, Office Action mailed May 24, 2011. |
U.S. Appl. No. 10/429,216, Office Action mailed Oct. 16, 2008. |
U.S. Appl. No. 10/429,216, Office Action mailed Sep. 15, 2010. |
U.S. Appl. No. 10/492,216, Office Action mailed Jan. 3, 2007. |
U.S. Appl. No. 10/544,093, Office Action mailed Feb. 9, 2009. |
U.S. Appl. No. 10/544,093, Office Action mailed Jan. 22, 2010. |
U.S. Appl. No. 10/544,093, Office Action, mailed Jun. 16, 2008. |
U.S. Appl. No. 10/625,854, Advisory Action mailed Jan. 8, 2008. |
U.S. Appl. No. 10/625,854, Examiner Interview Summary mailed Jun. 26, 2007. |
U.S. Appl. No. 10/625,854, Office Action mailed Aug. 23, 2006. |
U.S. Appl. No. 10/625,854, Office Action mailed Feb. 7, 2006. |
U.S. Appl. No. 10/625,854, Office Action mailed May 15, 2007. |
U.S. Appl. No. 10/625,854, Office Action mailed Nov. 10, 2005. |
U.S. Appl. No. 10/625,854, Office Action mailed Nov. 7, 2007. |
U.S. Appl. No. 10/703,713, Examiner Interview Summary mailed Feb. 21, 2006. |
U.S. Appl. No. 10/703,713, Examiner Interview Summary mailed Mar. 2, 2006. |
U.S. Appl. No. 10/703,713, Office Action mailed Jun. 2, 2006. |
U.S. Appl. No. 10/703,713, Office Action mailed Nov. 5, 2004. |
U.S. Appl. No. 10/703,713, Office Action mailed Sep. 27, 2005. |
U.S. Appl. No. 10/704,070, Office Action mailed Jun. 6, 2006. |
U.S. Appl. No. 10/704,070, Office Action mailed Nov. 5, 2004. |
U.S. Appl. No. 10/704,070, Office Action mailed Sep. 26, 2005. |
U.S. Appl. No. 10/771,174, Office Action mailed Aug. 23, 2007. |
U.S. Appl. No. 10/771,174, Office Action mailed Nov. 27, 2006. |
U.S. Appl. No. 10/771,174, Office Action mailed Sep. 14, 2006. |
U.S. Appl. No. 10/777,792, BPAI Decision mailed Aug. 30, 2010. |
U.S. Appl. No. 10/777,792, BPAI Decision on Request for Reconsideration mailed Nov. 30, 2010. |
U.S. Appl. No. 10/777,792, Examiner's Answer mailed Jul. 27, 2009. |
U.S. Appl. No. 10/777,792, Office Action mailed Apr. 3, 2008. |
U.S. Appl. No. 10/777,792, Office Action mailed Aug. 7, 2006. |
U.S. Appl. No. 10/777,792, Office Action mailed Mar. 2, 2006. |
U.S. Appl. No. 10/777,792, Office Action mailed May 8, 2007. |
U.S. Appl. No. 10/777,792, Office Action mailed Nov. 18, 2006. |
U.S. Appl. No. 10/777,792, Reply Brief Noted mailed Jan. 11, 2010. |
U.S. Appl. No. 10/788,666, Office Action mailed Dec. 15, 2005. |
U.S. Appl. No. 10/788,666, Office Action mailed Jan. 12, 2005. |
U.S. Appl. No. 10/789,273, Office Action mailed Sep. 22, 2006. |
U.S. Appl. No. 10/822,968, Office Action mailed Mar. 22, 2006. |
U.S. Appl. No. 10/823,463, Office Action mailed Feb. 4, 2005. |
U.S. Appl. No. 10/823,463, Office Action mailed Sep. 30, 2005. |
U.S. Appl. No. 10/828,548, Advisory Action mailed Jun. 8, 2007. |
U.S. Appl. No. 10/828,548, Office Action mailed Feb. 13, 2006. |
U.S. Appl. No. 10/828,548, Office Action mailed Feb. 4, 2005. |
U.S. Appl. No. 10/828,548, Office Action mailed Jun. 4, 2008. |
U.S. Appl. No. 10/828,548, Office Action mailed Oct. 24, 2006. |
U.S. Appl. No. 10/828,548, Office Action mailed Sep. 11, 2007. |
U.S. Appl. No. 10/828,548, Office Action mailed Sep. 29, 2005. |
U.S. Appl. No. 10/858,855 Office Action mailed Dec. 12, 2008. |
U.S. Appl. No. 10/858,855, Advisory Action mailed Apr. 7, 2008. |
U.S. Appl. No. 10/858,855, Office Action mailed Dec. 15, 2009. |
U.S. Appl. No. 10/858,855, Office Action mailed Jun. 22, 2006. |
U.S. Appl. No. 10/858,855, Office Action mailed Mar. 7, 2007. |
U.S. Appl. No. 10/858,855, Office Action mailed Nov. 23, 2007. |
U.S. Appl. No. 10/889,999, Office Action mailed Aug. 15, 2005. |
U.S. Appl. No. 10/889,999, Office Action mailed Jan. 5, 2005. |
U.S. Appl. No. 10/889,999, Office Action mailed Mar. 14, 2006. |
U.S. Appl. No. 10/890,000, Advisory Action mailed Jan. 14, 2008. |
U.S. Appl. No. 10/890,000, Office Action mailed Apr. 13, 2005. |
U.S. Appl. No. 10/890,000, Office Action mailed Mar. 10, 2006. |
U.S. Appl. No. 10/890,000, Office Action mailed Nov. 24, 2006. |
U.S. Appl. No. 10/890,000, Office Action mailed Sep. 19, 2005. |
U.S. Appl. No. 10/890,024, Office Action mailed Jun. 1, 2006. |
U.S. Appl. No. 10/890,024, Office Action mailed Nov. 2, 2005. |
U.S. Appl. No. 10/890,070, Office Action mailed Apr. 8, 2005. |
U.S. Appl. No. 10/890,070, Office Action mailed Jun. 1, 2006. |
U.S. Appl. No. 10/890,070, Office Action mailed Sep. 29, 2005. |
U.S. Appl. No. 10/890,071, Office Action mailed Dec. 18, 2006. |
U.S. Appl. No. 10/923,267, Office Action mailed Jul. 21, 2006. |
U.S. Appl. No. 10/923,469, Advisory Action mailed Apr. 6, 2009. |
U.S. Appl. No. 10/923,469, BPAI Decision mailed Feb. 22, 2011. |
U.S. Appl. No. 10/923,469, Examiner Interview Summary mailed Apr. 9, 2008. |
U.S. Appl. No. 10/923,469, Office Action mailed Dec. 29, 2008. |
U.S. Appl. No. 10/923,469, Office Action mailed Jul. 3, 2007. |
U.S. Appl. No. 10/923,469, Office Action mailed Mar. 24, 2008. |
U.S. Appl. No. 10/923,469, Office Action mailed Mar. 29, 2007. |
U.S. Appl. No. 10/923,469, Reply Brief Noted mailed Mar. 9, 2010. |
U.S. Appl. No. 10/923,471, Examiner Interview Summary mailed Oct. 20, 2008. |
U.S. Appl. No. 10/923,471, Office Action mailed Apr. 23, 2013. |
U.S. Appl. No. 10/923,471, Office Action mailed Apr. 24, 2008. |
U.S. Appl. No. 10/923,471, Office Action mailed Aug. 24, 2005. |
U.S. Appl. No. 10/923,471, Office Action mailed Dec. 29, 2006. |
U.S. Appl. No. 10/923,471, Office Action mailed Jan. 5, 2005. |
U.S. Appl. No. 10/923,471, Office Action mailed Jul. 31, 2007. |
U.S. Appl. No. 10/923,471, Office Action mailed Mar. 30, 2009. |
U.S. Appl. No. 10/923,471, Office Action mailed May 15, 2006. |
U.S. Appl. No. 10/923,474 Office Action mailed Aug. 4, 2006. |
U.S. Appl. No. 10/923,474, Advisory Action mailed Feb. 22, 2007. |
U.S. Appl. No. 10/923,474, Office Action mailed Feb. 15, 2005. |
U.S. Appl. No. 10/923,474, Office Action mailed Jun. 26, 2007. |
U.S. Appl. No. 10/923,474, Office Action mailed Nov. 17, 2005. |
U.S. Appl. No. 10/923,605, Office Action mailed Apr. 12, 2007. |
U.S. Appl. No. 10/928,926, Office Action mailed Jan. 12, 2007. |
U.S. Appl. No. 10/934,818, Office Action mailed Mar. 26, 2007. |
U.S. Appl. No. 10/934,819, Office Action mailed Jan. 24, 2006. |
U.S. Appl. No. 10/934,819, Office Action mailed Oct. 14, 2005. |
U.S. Appl. No. 11/058,757, Advisory Action mailed Mar. 5, 2007. |
U.S. Appl. No. 11/058,757, Office Action mailed Aug. 11, 2006. |
U.S. Appl. No. 11/058,757, Office Action mailed Aug. 24, 2005. |
U.S. Appl. No. 11/058,757, Office Action mailed May 3, 2005. |
U.S. Appl. No. 11/058,757, Office Action mailed Oct. 20, 2005. |
U.S. Appl. No. 11/108,102, Office Action mailed Jan. 11, 2006. |
U.S. Appl. No. 11/108,102, Office Action mailed Sep. 6, 2006. |
U.S. Appl. No. 11/244,678, Office Action mailed Apr. 18, 2007. |
U.S. Appl. No. 11/244,678, Office Action mailed Jul. 13, 2007. |
U.S. Appl. No. 11/244,678, Office Action mailed Mar. 24, 2008. |
U.S. Appl. No. 11/244,678, Office Action mailed Sep. 23, 2008. |
U.S. Appl. No. 11/245,524, filed Oct. 7, 2005, Schenk. |
U.S. Appl. No. 11/245,524, Office Action mailed Apr. 17, 2009. |
U.S. Appl. No. 11/245,524, Office Action mailed Dec. 10, 2010. |
U.S. Appl. No. 11/245,524, Office Action mailed Jun. 4, 2008. |
U.S. Appl. No. 11/245,524, Office Action mailed May 15, 2007. |
U.S. Appl. No. 11/245,524, Office Action mailed Sep. 27, 2007. |
U.S. Appl. No. 11/245,916, Advisory Action mailed May 15, 2007. |
U.S. Appl. No. 11/245,916, Advisory Action mailed Oct. 18, 2007. |
U.S. Appl. No. 11/245,916, filed Oct. 7, 2005, Schenk. |
U.S. Appl. No. 11/245,916, Office Action mailed Feb. 14, 2011. |
U.S. Appl. No. 11/245,916, Office Action mailed Jan. 13, 2006. |
U.S. Appl. No. 11/245,916, Office Action mailed Jan. 28, 2008. |
U.S. Appl. No. 11/245,916, Office Action mailed May 18, 2011. |
U.S. Appl. No. 11/245,916, Office Action mailed May 19, 2006. |
U.S. Appl. No. 11/245,916, Office Action mailed Oct. 31, 2008. |
U.S. Appl. No. 11/249,916, Office Action mailed Jan. 12, 2007. |
U.S. Appl. No. 11/260,047, Examiner Interview Summary mailed May 15, 2007. |
U.S. Appl. No. 11/260,047, Office Action mailed May 15, 2007. |
U.S. Appl. No. 11/260,047, Office Action mailed Oct. 26, 2006. |
U.S. Appl. No. 11/274,493, Office Action mailed Apr. 23, 2007. |
U.S. Appl. No. 11/274,493, Office Action mailed Nov. 2, 2007. |
U.S. Appl. No. 11/303,478, Office Action mailed Apr. 1, 2008. |
U.S. Appl. No. 11/303,478, Office Action mailed Jan. 31, 2014. |
U.S. Appl. No. 11/303,478, Office Action mailed Mar. 18, 2009. |
U.S. Appl. No. 11/303,478, Office Action mailed Oct. 16, 2008. |
U.S. Appl. No. 11/304,072, Office Action mailed Dec. 20, 2006. |
U.S. Appl. No. 11/304,986, Office Action mailed Dec. 31, 2008. |
U.S. Appl. No. 11/304,986, Office Action mailed Jan. 2, 2008. |
U.S. Appl. No. 11/305,889, Office Action mailed Apr. 4, 2008. |
U.S. Appl. No. 11/305,889, Office Action mailed Aug. 14, 2007. |
U.S. Appl. No. 11/305,889, Office Action mailed Jul. 25, 2008. |
U.S. Appl. No. 11/305,889, Office Action mailed May 23, 2008. |
U.S. Appl. No. 11/305,889, Office Action mailed May 4, 2007. |
U.S. Appl. No. 11/305,899Office Action mailed Dec. 10, 2008. |
U.S. Appl. No. 11/342,353, Office Action mailed Jul. 9, 2008. |
U.S. Appl. No. 11/342,353, Office Action mailed Mar. 26, 2008. |
U.S. Appl. No. 11/342,353, Office Action mailed Nov. 14, 2008. |
U.S. Appl. No. 11/348,353, Office Action mailed Jul. 22, 2008. |
U.S. Appl. No. 11/358,951, filed Feb. 22, 2006, Solomon et al. |
U.S. Appl. No. 11/396,391, filed Mar. 30, 2006, Schenk. |
U.S. Appl. No. 11/396,417, filed Mar. 30, 2006, Schenk. |
U.S. Appl. No. 11/454,772, Office Action mailed Dec. 21, 2007. |
U.S. Appl. No. 11/454,772, Office Action mailed Feb. 27, 2007. |
U.S. Appl. No. 11/454,772, Office Action mailed Jun. 27, 2007. |
U.S. Appl. No. 11/45772, Examiner Interview Summary mailed Apr. 13, 2007. |
U.S. Appl. No. 11/502,438, Office Action mailed Apr. 2, 2009. |
U.S. Appl. No. 11/516,724, Office Action mailed Jan. 17, 2009. |
U.S. Appl. No. 11/520,438, Office Action mailed Aug. 6, 2009. |
U.S. Appl. No. 11/707,639, Office Action mailed Apr. 3, 2009. |
U.S. Appl. No. 11/809,552, Office Action mailed Feb. 17, 2011. |
U.S. Appl. No. 11/841,794, filed Aug. 20, 2007, Warne et al. |
U.S. Appl. No. 11/841,832, filed Aug. 20, 2007, Warne et al. |
U.S. Appl. No. 11/841,849, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/841,857, filed Aug. 20, 2007, Warne et al. |
U.S. Appl. No. 11/841,882, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/841,897, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/841,919, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/841,919, Office Action mailed Mar. 28, 2011. |
U.S. Appl. No. 11/841,950, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/841,993, filed Aug. 20, 2007, Arumugham. |
U.S. Appl. No. 11/842,023, filed Aug. 20, 2007, Basi. |
U.S. Appl. No. 11/842,023, Office Action mailed Aug. 14, 2009. |
U.S. Appl. No. 11/842,023, Office Action mailed Nov. 13, 2008. |
U.S. Appl. No. 11/842,042, filed Aug. 20, 2007, Basi. |
U.S. Appl. No. 11/842,042, Office Action mailed Jun. 24, 2009. |
U.S. Appl. No. 11/842,056, filed Aug. 20, 2007, Basi. |
U.S. Appl. No. 11/842,056, Office Action mailed May 6, 2009. |
U.S. Appl. No. 11/842,085, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/842,085, Office Action mailed Apr. 14, 2009. |
U.S. Appl. No. 11/842,085, Office Action mailed Sep. 30, 2009. |
U.S. Appl. No. 11/842,101, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/842,113, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/842,113, Office Action mailed Aug. 24, 2010. |
U.S. Appl. No. 11/842,116, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/842,116, Office Action mailed Nov. 26, 2010. |
U.S. Appl. No. 11/842,120, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/842,120, Office Action mailed Apr. 14, 2009. |
U.S. Appl. No. 11/893,094, filed Aug. 20, 2007. |
U.S. Appl. No. 11/893,103, filed Aug. 20, 2007. |
U.S. Appl. No. 11/893,110, filed Aug. 20, 2007. |
U.S. Appl. No. 11/893,123, filed Aug. 20, 2007. |
U.S. Appl. No. 11/893,123, Office Action mailed May 11, 2011. |
U.S. Appl. No. 11/894,665, filed Aug. 20, 2007, Schenk. |
U.S. Appl. No. 11/894,714, filed Aug. 20, 2007, Basi. |
U.S. Appl. No. 11/894,754, filed Aug. 20, 2007. |
U.S. Appl. No. 11/894,789, filed Aug. 20, 2007, Basi. |
U.S. Appl. No. 12/037,045, filed Feb. 25, 2008, Seubert. |
U.S. Appl. No. 12/037,045, Office Action mailed Apr. 28, 2010. |
U.S. Appl. No. 12/106,206, filed Apr. 18, 2008, Schroeter. |
U.S. Appl. No. 12/106,206, Office Action mailed Jul. 9, 2010. |
U.S. Appl. No. 12/181,238, Examiner Interview Summary mailed Mar. 5, 2010. |
U.S. Appl. No. 12/181,238, Office Action mailed May 28, 2009. |
U.S. Appl. No. 12/253,929, Office Action mailed Apr. 28, 2010. |
U.S. Appl. No. 12/297,636, Office Action mailed Oct. 15, 2012. |
U.S. Appl. No. 12/336,340, Office Action mailed Mar. 4, 2010. |
U.S. Appl. No. 12/608,869, Office Action mailed Oct. 25, 2011. |
U.S. Appl. No. 12/738,396, Office Action mailed Feb. 13, 2012. |
U.S. Appl. No. 12/738,396, Office Action mailed Sep. 21, 2012. |
U.S. Appl. No. 12/977,013, Office Action mailed Jan. 6, 2012. |
U.S. Appl. No. 12/977,013, Office Action mailed Jul. 1, 2013. |
U.S. Appl. No. 13/076,379, Office Action mailed Nov. 28, 2012. |
U.S. Appl. No. 13/123,898, Office Action mailed Apr. 17, 2013. |
U.S. Appl. No. 13/123,898, Office Action mailed Jul. 20, 2012. |
U.S. Appl. No. 13/270,015, Office Action mailed Jun. 19, 2013. |
U.S. Appl. No. 13/271,081, Office Action mailed Mar. 1, 2013. |
U.S. Appl. No. 60/067,219, filed Dec. 3, 1997, Weiner et al. |
U.S. Appl. No. 60/067,740, filed Dec. 2, 1997, Schenk. |
U.S. Appl. No. 60/079,697, filed Mar. 27, 1998, Weiner et al. |
U.S. Appl. No. 60/080,970, filed Jan. 11, 1999, Schenk. |
U.S. Appl. No. 60/136,655, filed May 28, 1999, Brayden. |
U.S. Appl. No. 60/137,010, filed Jun. 1, 1999, Schenk. |
U.S. Appl. No. 60/137,047, filed Jun. 1, 1999, Hirtzer. |
U.S. Appl. No. 60/139,408, filed Jun. 16, 1999, Raso. |
U.S. Appl. No. 60/168,594, filed Nov. 29, 1999, Chalifour et al. |
U.S. Appl. No. 60/169,687, filed Dec. 8, 1999, Chain. |
U.S. Appl. No. 60/184,601, filed Feb. 24, 2000, Holtzman et al. |
U.S. Appl. No. 60/186,295, filed Mar. 1, 2000, Rasmussen et al. |
U.S. Appl. No. 60/251,892, filed Dec. 6, 2000, Basi et al. |
U.S. Appl. No. 60/254,465, filed Dec. 8, 2000, Holtzman et al. |
U.S. Appl. No. 60/254,498, filed Dec. 8, 2000, Holtzman et al. |
U.S. Appl. No. 60/363,751, filed Mar. 12, 2002, Basi. |
U.S. Appl. No. 60/444,150, filed Feb. 1, 2003, Yednock. |
U.S. Appl. No. 60/474,654, filed May 30, 2003, Basi. |
U.S. Appl. No. 60/530,480, filed Dec. 17, 2003, Arumugham. |
U.S. Appl. No. 60/530,481, filed Dec. 17, 2003, Arumugham. |
U.S. Appl. No. 60/616,474, filed Oct. 5, 2004, Sinacore. |
U.S. Appl. No. 60/622,525, filed Oct. 26, 2004, Pavliakova. |
U.S. Appl. No. 60/636,684, filed Dec. 15, 2004, Basi. |
U.S. Appl. No. 60/636,687, filed Dec. 15, 2004, Johnson-Wood. |
U.S. Appl. No. 60/636,776, filed Dec. 15, 2004, Basi. |
U.S. Appl. No. 60/636,810, filed Dec. 15, 2004, Jacobson. |
U.S. Appl. No. 60/636,842, filed Dec. 15, 2004, Jacobson. |
U.S. Appl. No. 60/637,138, filed Dec. 16, 2004, Jacobson. |
U.S. Appl. No. 60/637,253, filed Dec. 16, 2004, Jacobson. |
U.S. Appl. No. 60/648,631, filed Jan. 28, 2005, Luisi et al. |
U.S. Appl. No. 60/648,639, filed Jan. 28, 2005, Luisi et al. |
U.S. Appl. No. 60/691,821, filed Jun. 17, 2005, Godavarti. |
U.S. Appl. No. 60/735,687, filed Nov. 10, 2005, Jacobson. |
U.S. Appl. No. 60/736,045, filed Nov. 10, 2005, Johnson-Wood. |
U.S. Appl. No. 60/736,119, filed Nov. 10, 2005, Jacobson. |
U.S. Appl. No. 60/793,014, filed Apr. 18, 2006, not named. |
U.S. Appl. No. 60/925,228. |
U.S. Appl. No. 60/999,423, filed Oct. 17, 2007, Black. |
Ulvestad et al., "Fc Receptors for IgG on Cultured Human Microglia Mediate Cytotoxicity and Phagocytosis of Antibody-coated Targets," Journal of Neuropathology and Experimental Neurology, 53(1):27-36 (1994). |
UniProtKB/Swiss-Prot entry P18525, pp. 1-3 downloaded from http://www.expasy.org/cgi-bin/niceprot.pl/printable?ac=P18525 on Feb. 8, 1997, "HV54—Mouse" (Nov. 1, 1990). |
Urmoneit et al., "Cerebrovascular Smooth Muscle CElls Internalize Alzheimer Amyloid Beta Protein via a Lipoprotein Pathway: Implications for Cerebral Amyloid Angiopathy," Laboratory Investigation, 77(2):157-166 (1997). |
Vajdos et al., "Comprehensive Functional Maps of the Antigen-binging site of an Anti—ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis," J. Mol. Biol., 320:415-428 (2002). |
Valleix et al., "Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family," Kidney International, 61:907-912 (2002). |
Van Dam et al., "Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model" Psychopharmacology 180:177-190 (2005). |
Van Den Dobbelsteen et al., "Characteristics of Immune Responses to Native and Protein Conjugated Pneumococcal Polysaccharide Type 14," Scand. J. Immunol., 41:273-280 (1995). |
Van Gool et al., "Concentrations of amyloid-β protein in cerebrospinal fluid increase with age in patients free from neurodegenerative disease," Neuroscience Letters, 172:122-124 (1994). |
Van Leuven, F., "Single and multiple transgenic mice as models for alzheimer's disease," Progress in Neurobiology, 61:305-312 (2000). |
Van Noort, Multiple sclerosis: an altered immune response or an altered stress response?, J Mol Med 74:285-296 (1996). |
Van Regenmortel et al, "D-peptides as immunogens and diagnostic reagents," Curr. Opin. Biotechnol., 9(4):377-382 (1998). |
Vanderstichele et al., "Standardization of Measurement of B-amyloid(1-42) in Cerebrospinal Fluid and Plasma:," Int. J. Exp. Clin. Invest., 7(4):245-258 (2000). |
Vanengelen, et al "Immunoglobulin treatment in human and experimental epilepsy" J of Neuro (1994); 57 (supplement):72-75. |
Vastag, "Monoclonals expand into neural disorders" Nature 24:6 p. 595-596 (Jun. 2006). |
Vehmas et al., "beta-Amyloid peptide vaccination results in marked changes in serum and brain Abeta levels in APPswe/PS1 DeltaE9 mice, as detected by SELDI-TOF-based ProteinChip® technology," Dna Cell Biol., (11):713-721 (2001). |
Velazquez et al., "Aspartate residue 7 in amyloid β-protein is critical for classical complement pathway activation: Implications for Alzheimer's disease pathogenesis," Nature Medicine, 3(1):77-79. |
Verbeek et al., "Accumulation of Intercellular Adhesion Molecule-1 in Senile Plaques in Brain Tissue of patients with Alzheimer's Disease," Amer. Journ. Pathology, 144(1):104-116 (1994). |
Verma et al., "Gene therapy—promises, problems and prospects," Nature, 389:239-242 (1997). |
Vershigora A. E. Obshchaya Immynologiya, pp. 35, 229-231 and 152-153. |
Vickers, J. C., "A Vaccine Against Alzheimer's Disease," Drugs Aging, 19(7):487-494 (2002). |
Vidanovic et al., "Effects of nonionic surfactants on the physical stability of immunoglobulin G in aqueous solution during mechanical agitation," DIE PHARMAZIE, 58(6):399-404 (2003). |
Viswanathan et al., "Cerebral Microhemorrhage", Stroke., 37:550-555 (2006). |
Walker et al., "Labeling of Cerebral Amyloid in Vivo with a Monoclonal Antibody," J. Neuropath Exp. Neurology, 53(4):377-383 (1994). |
Walls, et al., "Autoantibody responses in the cerebrospinal fluid of guinea pigs with chronic relapsing experimental allergic encephalomyelitis", Acta Neruol. Scan., 78:422-428 (1988). |
Walsh et al., "Naturally secreted oligomers of amyloid βprotein potently inhibit hippocampal longterm potentiation in vivo," Nature, 416(6880):535-539 (2002). |
Wang et al, "Site-specific UBITh amyloid-β vaccine for immunotherapy of Alzheimer's disease" Vaccine 25 (2007) 3041-3052. |
Wang et al., "Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rate dentate gyrus," Brain Research, 924:133-140 (2002). |
Wang et al., "The levels of soluble versus insoluble brain Aβ distinguish Alzheimer's disease from normal and pathologic aging," Experimental Neurology, 158:328-337 (1999). |
Wang, W., "Instability, stabilization, and formulation of liquid protein pharmaceuticals," Int. J. Pharmaceutics, 185(2):129-188 (1999). |
Ward et al., "Spontaneous Deletions in IG Heavy Chain Genes Flaking Seuences Influence Splice Site Selection Nucleic Acids Research," 19(23): 6475-6480 (1991). |
Washington University in St. Louis School of Medicine, "Study gives Clues to Working of Anti-Alzheimer Antibody," downloaded from www.medicine.wustl.edu/˜wumpa/news on Dec. 15, 2004. |
Webster's New World Dictionary of American English, Third College Edition, p. 1078 (1988). |
Webster's New World Dictionary, p. 1387, therapeutic (1988). |
Wehner, Declaration May 21, 2007. |
Weiner et al., "Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease," Annals of Neurology, 48:567-579 (2000). |
Weiner et al., "Oral Tolerance: Immunologic Mechanisms and Treatment of Animal and Human Organ-Specific Autoimmune Diseases by Oral Administration of Autoantigens," Annu. Rev. Immunol., 12:809-837 (1994). |
Weiner, H. L., "Oral tolerance: immune mechanisms and treatment of autoimmune diseases," Immunology Today, 18:335-343 (1997). |
Weinreb et al., "NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded," Biochemistry, 35(43):13709-13715 (1996). |
Weissmann et al., "Bovine spongiform encephalopathy and early onset variant Creutzfeldt-Jakob disease," Curr. Opin. Neurobiol., 7:695-700 (1997). |
Weldon et al., "Neurotoxicity of Aβ Peptide: Confocal Imaging of Cellular Changes Induced by—Amyloid in Rat CNS In Vivo," Society for Neuroscicence Abstracts, 22(Part 1) (1996). |
Welling et al., "Choice of Peptide and Peptide Length for the Generation of Antibodies Reactive With the Intact Protein," FEBS Letters, 182(1):81-84 (Mar. 1985). |
Wells, J. A., "Additivity of Mutational Effects in Proteins," Biochemistry, 29(37):8509-8517 (1990). |
Wen, G.Y., "Alzheimer's Disease and Risk Factors," J. Food Drug Analysis 6(2):465-476 (1998). |
Wengenack et al., "Targeting Alzheimer amyloid plaques in vivo," Nature Biotech., 18:868-872 (2000). |
Weyer, et al., "A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease", Neuropsychobiology, 36(2):73-82, Abstract only (Jan. 1997). |
Whitcomb et al., "Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain," Am J Pysiol Gaastrointest Liver Physiol, 259:G6878-G691 (1990). |
Whitcomb et al., "Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain," Am J Pysiol Gastrointest Liver Physiol, 259:G687-G691 (1990). |
White et al., "Immunotherapy as a therapeutic treatment for neurodegenerative disorders," J. Neurochem., 87(4):801-808 (2003). |
Wick et al., "The Aging Immune System: Primary and Secondary Alterations of Immune Reactivity in the Elderly" Exp. Geronology, vol. 32, Nos. 4/5, pp. 401-413, 1997. |
Wiessner, et al "The Second-Generation Active Aβ Immunotherapy CAD106 Reduces Amyloid Accumulation in APP Transgenic Mice While Minimizing Potential Side Effects", J. Neurosci. 31(25):9323-9331 (2011). |
Wikipedia definition of "antigen" printed from internet on Apr. 26, 2006. |
Wikipedia definition of "epitope" printed from internet on Apr. 26, 2006. |
Wikipedia definition of "route of administration including parenteral" printed from intemet on Apr. 26, 2006. |
Wikipedia entry for "Monoclonal antibody therapy" accessed on Sep. 22, 2011. |
Wikipedia entry for Antibody, retrieved Apr. 27, 2009 from http://en.wikipedia.org/wiki/Antibody. |
Wilcock, et al. "Deglycosylated anti-Amyloid-β Antibodies Eliminate Cognitive Deficits and Reduce Parenchymal Amyloid with Minimal Vascular Consequences in Aged Amyloid Precursor Protein Transgenic Mice" Neurobiology of Disease 26(20:5340-5346 (May 17, 2006). |
Wilcock, et al. "Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition" The Journal of Neuroscience, Jul. 7, 2004 24(27):6144-6151. |
Wilcock, et al., "Number of AB Inoculations in APP+PSI Transgenic Mice Influences Antibody Titers, Microglial Activation, and Congophilic Plaque Levels" DNA and Celll Biology, vol. 20 No. 11: 731-736 (2001). |
Wilson et al., "Phage display: applications, innovations, and issues in phage and host biology," Can. J. Microbiol, 44:313-329 (1998). |
Winblad et al., "Hints of a therapeutic Vaccine for Alzheimer's?" Neuron, 38:517-519 (2003). |
Winter et al., "Humanized antibodies" Immunology Today, 14(6):243-246 (1996). |
Wisconsin Alumni Research Foundation, "Injection of Newborn Mice with Seven Chemical Adjuvants to Help Determine Their Safety in Use in Biologicals", U.S. Govt. Res. Develop. Rep., 70(24), 56. (Publication date unknown.). |
Wisniewski et al., "Alzheimer's disease and soluble A beta," Neurobiol. Aging, 15(2):143-52 (1994). |
Wisniewski et al., "Therapeutics in Alzheimer's and Prion Diseases,"Biochemical Society Transactions, 30(4):574-587 (2002). |
Wong et al., "Neuritic Plaques and Cerebrovascular Amyloid in Alzheimer Disease are Antigenically Related " PNAS, 82:8729-8732 (1985). |
Wood et al., "Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease," PNAS, 94: 1550-1555 (1997). |
Wood et al., "Prolines and amyloidogenicily in fragments of the Alzheimer's peptide β/A4" Biochemistry, 34:724-730 (1995). |
Wu et al., "An Analysis of the Sequences of the Variable Regions of Bence Jones Proteins and Myeloma Light Chains and their Implications for Antibody Complementarity*," J. Exp. Med., 132:211-250 (1970). |
Wu et al., "Expression of immunogenic epitopes of hepatitis B surface antigen with hybrid flagellin proteins by a vaccine strain of Salmonella" PNAS, 86:4726-4730 (1989). |
Wu et al., "Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues," J. Mol. Biol., 294:151-162 (1999). |
Wu et al., "Saponin Adjuvant Enhancement of Antigen-Specific Immune Responses to an Experimental HIV-1 Vaccine" J of Immunology 149:1519-1525 (1992). |
Wu, et al., "Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor," J. Clin. Invest., 100:1804-1812 (1997). |
Wyeth, Annual Review 2005: Creating Value . . . Advancing Health (Feb. 27, 2006). |
Xiang et al., "Manipulation of the immune response to a plasmid-encoded viral antigen by coinoculation with plasmids expressing cytokines," Immunity, 2(2):129-135 Abstract (1995). |
Xu et al., "Increased incidence of anti-β-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer's disease," Mechanisms of Ageing and Development, 94:213-222 (1997). |
Yamada et al., "Generation and Characterization of Rat Monoclonal Antibodies Against Human Serum Amyloid A," Scand. J. Immunol., 46(2):175-179 (1997). |
Yamaguchi et al., Diffuse plaques assoiated with astroglial amyloid β protein, possibly showing a disappearing stage of senile plaques, Acta Neuropathol., 95:217-222 (1998). |
Yanagisawa K et al., "Amyloid BETA-protein (Alpha-Beta) associated with lipid molecules: immunoreactivity distinct from that of soluble Alpha-Beta," FEBS Letters, 1(420): 43-46 (1997). |
Yang et al., "Effects of Racemization on the Aggregational Properties of the Amyloid β-Peptide in Alzheimer's Disease," abstract # 255 from American Chemical Society 214th National Meeting (1997). |
Yang et al., "Monoclonal Antibody to the C-terminus of Beta-Amyloid," Neuroreport, 16(5):2117-2120 (1994). |
Yankner et al., "Neurotrophic and Neurotoxic effects of Amyloid β Protein: Reversal by Tachykinin Neuropeptides," Science, 250:279-282 (1990). |
Younkin, "Amyloid β vaccination: reduced plaques and improved cognition" Nature Medicine, 7:18-19 (2001). |
Zameer et al., "Single Chain Fv Antibodies against 25-35 Peptide Fragment of Amyloid-β: Potential Therapeutic for Alzheimer's Disease," Abstract P4-420, p. S593, presented at Poster Session P4:Therapeutics and Therapeutic Strategies-Therapeutic Strateies, Amyloid-Based. |
Zhang et al., "A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and β-amyloid plaques in a mouse model of Alzheimer's disease," Neurobiology of Disease, 14:365-379 (2003). |
Zhang et al., "Specialized Applications, Purification of Recombinant Proteins and Study of Proteins and Study of Interation by Epitope Tagging," Current Protocols in Mol. Biol., Supp 41, pp. 10.15.1 through 10.15.9 (1998). |
Zhao et al., "Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism", Neurobiology of disease (Mar. 18, 2009) 29(11):3603-3612. |
Zlokovic et al., "Blood-Brain Barrier Transport of Circulating Alzheimer's Amyloid β." Biochemical and Biophysical Research Communications. vol. 197, No. 3, pp. 1034-1040 (1993). |
Zlokovic et al., "Clearance of amyloid β-peptide from brain: transport or metabolism?," Nature Medicine, 6(7):718-719 (2000). |
Zlokovic et al., "Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers," PNAS, 93(9):4229-4334 (1996) abstract only. |
Zotova et al., "Inflammation in Azheimer's disease: relevance to pathogenesis and therapy" Alzheimer's Research & Therapy 2:1 p. 2-9 (2010). |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160120941A1 (en) * | 2013-05-31 | 2016-05-05 | Regeneron Pharmaceuticals, Inc. | Methods of using il-1 antagonists to treat alzheimer's disease |
US20180319856A1 (en) * | 2015-11-09 | 2018-11-08 | The University Of British Columbia | Epitopes in amyloid beta mid-region and conformationally-selective antibodies thereto |
US10759837B2 (en) * | 2015-11-09 | 2020-09-01 | The University Of British Columbia | Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide |
US10774120B2 (en) * | 2015-11-09 | 2020-09-15 | The University Of British Columbia | Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide |
US10772969B2 (en) | 2015-11-09 | 2020-09-15 | The University Of British Columbia | N-terminal epitopes in amyloid beta and conformationally-selective antibodies thereto |
US11905318B2 (en) | 2015-11-09 | 2024-02-20 | The University Of British Columbia | Cyclic compound/peptide comprising an A-beta13-16 peptide and a linker that is covalently coupled to the n-terminus residue and the c-terminus residue of the A-beta13-16 peptide |
US11970522B2 (en) | 2015-11-09 | 2024-04-30 | The University Of British Columbia | Cyclic compound/peptide comprising an A-beta15-18 peptide and a linker that is covalently coupled to the n-terminus residue and the c-terminus residue of the A-BETA15-18 peptide |
US10751382B2 (en) | 2016-11-09 | 2020-08-25 | The University Of British Columbia | Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide |
US11779629B2 (en) | 2016-11-09 | 2023-10-10 | The University Of British Columbia | Compositions comprising cyclic peptides derived from an A-beta peptide |
WO2022192636A1 (fr) | 2021-03-12 | 2022-09-15 | Eli Lilly And Company | Anticorps anti-amyloïde bêta et leurs utilisations |
WO2022251048A1 (fr) | 2021-05-24 | 2022-12-01 | Eli Lilly And Company | Anticorps anti-amyloïde bêta et leurs utilisations |
Also Published As
Publication number | Publication date |
---|---|
HK1109585A1 (en) | 2008-06-13 |
PE20061329A1 (es) | 2006-12-08 |
UY29284A1 (es) | 2006-06-30 |
JP2012024098A (ja) | 2012-02-09 |
EP1838348A1 (fr) | 2007-10-03 |
EP1838348B1 (fr) | 2013-06-26 |
US20060198851A1 (en) | 2006-09-07 |
AR052051A1 (es) | 2007-02-28 |
ES2434732T3 (es) | 2013-12-17 |
CA2590337C (fr) | 2017-07-11 |
TW200635607A (en) | 2006-10-16 |
WO2006066089A1 (fr) | 2006-06-22 |
JP2008523815A (ja) | 2008-07-10 |
CA2590337A1 (fr) | 2006-06-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8916165B2 (en) | Humanized Aβ antibodies for use in improving cognition | |
US7625560B2 (en) | Humanized antibodies that recognize beta amyloid peptide | |
US20060257396A1 (en) | Abeta antibodies for use in improving cognition | |
US7871615B2 (en) | Humanized antibodies that recognize beta amyloid peptide | |
US8128928B2 (en) | Humanized antibodies that recognize beta amyloid peptide | |
JP2012050437A (ja) | ベータアミロイドペプチドを認識するヒト化抗体 | |
JP2012233002A (ja) | 認知の改善における使用のためのアミロイドβ抗体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ELAN PHARMACEUTICALS, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BASI, GURIQ;REEL/FRAME:017732/0636 Effective date: 20050331 Owner name: NEURALAB LIMITED, BERMUDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ELAN PHARMACEUTICALS, INC.;REEL/FRAME:017732/0611 Effective date: 20060331 Owner name: WYETH, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:JACOBSEN, JACK STEVEN;REEL/FRAME:017732/0623 Effective date: 20060308 |
|
AS | Assignment |
Owner name: ELAN PHARMA INTERNATIONAL LIMITED, IRELAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NEURALAB LIMITED;REEL/FRAME:022999/0692 Effective date: 20090717 |
|
AS | Assignment |
Owner name: ELAN PHARMA INTERNATIONAL LIMITED, IRELAND Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE PREVIOUSLY RECORDED ON REEL 022999 FRAME 0692;ASSIGNOR:NEURALAB LIMITED;REEL/FRAME:023437/0916 Effective date: 20090717 Owner name: WYETH, NEW JERSEY Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE PREVIOUSLY RECORDED ON REEL 022999 FRAME 0692;ASSIGNOR:NEURALAB LIMITED;REEL/FRAME:023437/0916 Effective date: 20090717 Owner name: CRIMAGUA LIMITED, IRELAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ELAN PHARMA INTERNATIONAL LIMITED;REEL/FRAME:023437/0926 Effective date: 20090914 Owner name: WYETH, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ELAN PHARMA INTERNATIONAL LIMITED;REEL/FRAME:023437/0926 Effective date: 20090914 Owner name: JANSSEN ALZHEIMER IMMUNOTHERAPY, IRELAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CRIMAGUA LIMITED;REEL/FRAME:023437/0936 Effective date: 20090914 Owner name: WYETH, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CRIMAGUA LIMITED;REEL/FRAME:023437/0936 Effective date: 20090914 Owner name: WYETH, NEW JERSEY Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE PREVIOUSLY RECORDED ON REEL 022999 FRAME 0692. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST;ASSIGNOR:NEURALAB LIMITED;REEL/FRAME:023437/0916 Effective date: 20090717 Owner name: ELAN PHARMA INTERNATIONAL LIMITED, IRELAND Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE PREVIOUSLY RECORDED ON REEL 022999 FRAME 0692. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST;ASSIGNOR:NEURALAB LIMITED;REEL/FRAME:023437/0916 Effective date: 20090717 |
|
AS | Assignment |
Owner name: WYETH LLC,NEW JERSEY Free format text: CHANGE OF NAME;ASSIGNOR:WYETH;REEL/FRAME:024160/0365 Effective date: 20091109 Owner name: WYETH LLC, NEW JERSEY Free format text: CHANGE OF NAME;ASSIGNOR:WYETH;REEL/FRAME:024160/0365 Effective date: 20091109 |
|
CC | Certificate of correction | ||
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.) |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Expired due to failure to pay maintenance fee |
Effective date: 20181223 |